Dosimetry Characterization and Early-Phase Dose and Injury-Severity Biomarkers in a Rhesus Macaque Dose-Response Model System
Main Article Content
Abstract
The purpose of this study was to characterize radiation dosimetry and validate early-phase radiation biomarkers using a Rhesus macaque (Macaca mulatta) non-human-primate radiation model. Non-human-primates in pairs (male and females; 4.4 to 7.8 kg; 3.6 to 5.9 y) were exposed bilaterally to 60Co-gamma rays to midline doses of 0, 1, 3.5, 6.5 and 8.5 Gy at ~0.55 Gy/min (n = 6/dose). The exposure intervals were determined based on dose-rate measurements using cylindrical water phantoms with the alanine – electron paramagnetic resonance system traceable to the National Institute of Standards and Technology. Field uniformity was characterized and the physics reference doses were measured at the mid-line at the height of the xiphoid process. Blood was sampled for measurements of hematology and blood chemistry radio-responses prior to irradiation and up to 4 d after exposure. The field in the area occupied by the animals was uniform within approximately ± 0.5% in the lateral direction, within approximately ± 1.5% in the anterior-posterior direction, and within approximately ± 2% in the superior-inferior direction. Exposure to 1, 3.5, 6.5, and 8.5 Gy causes a dramatic increase in amylase activity (~1.9, ~3.1, ~8.3, ~13.3 fold, respectively) at 1 d after exposure (p= <0.001) along with more than 60, 80, and 90% depletion of lymphocyte at 1, 3.5, and higher doses 6.5 or 8.5 Gy, respectively. Hematological (i.e., lymphocyte depletion and increases in neutrophil to lymphocyte ratios at 1-3 d) and blood chemistry (i.e., serum amylase activity at 1 d) radiation biomarkers demonstrate useful diagnostic utility for life-threatening radiation exposure assessment.
Keywords:
biodosimetry, 60Co-γ-rays, rhesus macaque, hematology, amylase activity, radiation dosimetry, alanine, electron paramagnetic resonance
Article Details
How to Cite
RAHMAN, Arifur et al.
Dosimetry Characterization and Early-Phase Dose and Injury-Severity Biomarkers in a Rhesus Macaque Dose-Response Model System.
Medical Research Archives, [S.l.], v. 13, n. 8, sep. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6676>. Date accessed: 06 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i8.6676.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Dainiak N, Waselenko JK, Armitage JO, MacVittie TJ, Farese AM. The hematologist and radiation casualties. Hematology Am Soc Hematol Educ Program. 2003:473-96. doi:10.1182/asheducation-2003.1.473
2. Waselenko JK, MacVittie TJ, Blakely WF, et al. Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Ann Intern Med. Jun 15 2004;140(12):1037-51. doi:10.7326/0003-4819-140-12-200406150-00015
3. Blakely WF, Salter CA, Prasanna PG. Early-response biological dosimetry--recommended countermeasure enhancements for mass-casualty radiological incidents and terrorism. Health Phys. Nov 2005;89(5):494-504. doi:10.1097/01.hp.0000175913.36594.a4
4. Goans RE, Waselenko JK. Medical management of radiological casualties. Health Phys. Nov 2005;89(5):505-12. doi:10.1097/01.hp.0000172144.94491.84
5. Swartz HM, Iwasaki A, Walczak T, et al. Measurements of clinically significant doses of ionizing radiation using non-invasive in vivo EPR spectroscopy of teeth in situ. Appl Radiat Isot. Feb 2005;62(2):293-9. doi:10.1016/j.apradiso.2004.08.016
6. National Council of Radiation Protection and Measurements. Measurement of persons accidentally contaminated with radionuclides. 1994. NCPR Report No 65. Available from: https://www.biblio.com/book/management-persons-accidentally-contaminated-radionuclides-recommendations/d/1045854443?srsltid=AfmBOoowq2iw28ZSA-lpZJ534sWt9rMJTb_GRMYeZmIqLbRNAyyjW0mm
7. National Council of Radiation Protection and Measurements. Management of terrorist events involving radioactive material. 2001. NCPR Report No 138. Available from: https://ncrponline.org/shop/reports/report-no-138-management-of-terrorist-events-involving-radioactive-material-2001/
8. National Council of Radiation Protection and Measurements. Key elements of preparing emergency responders for nuclear and radiological terrorism. 2005. NCRP Commentary No 19. Available from: https://ncrponline.org/shop/commentaries/commentary-no-19-key-elements-of-preparing-emergency-responders-for-nuclear-and-radiological-terrorism-2005/
9. Cohen KS. In: Gusev AE, Guskova AK, Mettler FA, Jr., eds. Medical management of radiation accidents. 2nd ed. CRC Press; 2001:chap Acute radiation sickness: underlying principles and assessment. Available from: https://www.taylorfrancis.com/chapters/mono/10.1201/9781420037197-10/acute-radiation-sickness-underlying-principles-assessment-kenneth-cohen-igor-gusev-angelina-guskova-fred-mettler
10. Blakely WF, Port M, Abend M. Early-response multiple-parameter biodosimetry and dosimetry: risk predictions. J Radiol Prot. Dec 6 2021;41(4)doi:10.1088/1361-6498/ac15df
11. Fliedner TM. Nuclear terrorism: the role of hematology in coping with its health consequences. Curr Opin Hematol. Nov 2006;13(6):436-44. doi:10.1097/01.moh.0000245696.77758.e6
12. Fliedner TM, Graessle D, Meineke V, Dorr H. Pathophysiological principles underlying the blood cell concentration responses used to assess the severity of effect after accidental whole-body radiation exposure: an essential basis for an evidence-based clinical triage. Exp Hematol. Apr 2007;35(4 Suppl 1):8-16. doi:10.1016/j.exphem.2007.01.006
13. Goans RE, Holloway EC, Berger ME, Ricks RC. Early dose assessment following severe radiation accidents. Health Phys. Apr 1997;72(4):513-8. doi:10.1097/00004032-199704000-00001
14. Goans RE, Holloway EC, Berger ME, Ricks RC. Early dose assessment in criticality accidents. Health Phys. Oct 2001;81(4):446-9. doi:10.1097/00004032-200110000-00009
15. Azizova TV, Osovets SV, Day RD, et al. Predictability of acute radiation injury severity. Health Phys. Mar 2008;94(3):255-63. doi:10.1097/01.HP.0000290833.66789.df
16. Blakely WF, Ossetrova NI, Mangalapus GL, et al. Amylase and blood cell-count hematological radiation-injury biomarkers in a rhesus monkey radiation model use of multiperameter and integrated biological dosimentry. Radiation Measurements. 2007;42(6-9):1164-1170. doi:10.1016/j.radmeas.2007.05.013
17. Blakely WF, Ossetrova NI, Whitnall MH, et al. Multiple parameter radiation injury assessment using a nonhuman primate radiation model-biodosimetry applications. Health Phys. Feb 2010;98(2):153-9. doi:10.1097/HP.0b013e3181b0306d
18. Nagy V, Parra NC, Shoemaker MO, Elliott TB, Ledney GD. Alanine dosimetry accurately determines radiation dose in nonhuman primates. Armed Forces Radiobiology Research Institute Special Publication. 2007:1-32.
19. Ossetrova NI, Blakely WF, Nagy V, et al. Non-human primate total-body irradiation model with limited and full medical supportive care including filgrastim for biodosimetry and injury assessment. Radiat Prot Dosimetry. Dec 2016;172(1-3):174-191. doi:10.1093/rpd/ncw176
20. Woods MJ, Collins SM. Half-life data-a critical review of TECDOC-619 update. Appl Radiat Isot. Feb-Apr 2004;60(2-4):257-62. doi:10.1016/j.apradiso.2003.11.026
21. International Standardization Organization and ASTM International. ISO/ASTM 51607:2004. Vol. 51607:2004(E). 2004. Standard practice for use of an alanine-EPR dosimetry system. Available from: https://www.iso.org/standard/39026.html
22. International Standardization Organization and ASTM International. ISO/ASTM 51607:2013. Vol. 51607:2013(E). 2013. Standard practice for use of an alanine-EPR dosimetry system. Available from: https://www.iso.org/standard/62955.html
23. Nagy V. Accuracy considerations in alanine dosimetry. Appl Radiat Isot. May 2000;52(5):1039-1050. doi:10.1016/S0969-8043(00)00052-X
24. Nagy V, Puhl JM, Desrosiers MF. Advancements in accuracy of the alanine dosimetry system. Part 2. The influence of the irradiation temperature. Radiat Phys Chem. 2000;57(1):1-9. doi:10.1016/S0969-806X(99)00339-4
25. Nagy V, Sleptchonok OF, Desrosiers MF, Weber RT, Heiss AH. Advancements in accuracy of the alanine EPR dosimetry system. Part III: Usefulness of an adjacent reference sample. Appl Radiat Isot. 2000;59(4):429-441. doi:10.1016/S0969-806X(00)00275-9
26. National Research Council. Guide for the care and use of laboratory animals. 8th ed. National Academies Press; 2011.
27. Weatherall D, Working Group. The use of non-human primates in research. 2006:149. A working group report chaired by Sir David Weatherall FMedSci. 2006. Available from: https://acmedsci.ac.uk/file-download/34945-1165861003.pdf
28. King GL, Sandgren DJ, Mitchell JM, Bolduc DL, Blakely WF. System for scoring severity of acute radiation syndrome response in rhesus macaques (Macaca mulatta). Comp Med. Dec 1 2018;68(6):474-488. doi:10.30802/AALAS-CM-17-000106
29. Nagy V, Desrosiers MF. Complex time dependence of the EPR signal of irradiated L-α-alanine. Appl Radiat Isot. 1996;47(8):789-793. doi:10.1016/0969-8043(96)00053-X
30. Shleien B, Slaback LA, Jr., Birky BK. Handbook of health physics and radiological health. 3rd ed. Williams & Wilkins; 1998. Available from: https://books.google.com/books/about/Handbook_of_Health_Physics_and_Radiologi.html?id=j2vGQgAACAAJ
31. Fanton JW, Golden JG. Radiation-induced endometriosis in Macaca mulatta. Radiat Res. May 1991;126(2):141-6. doi:10.2307/3577812
32. Hardy KA. Dosimetry methods used in the studies of the effects of protons on primates: a review. Radiat Res. May 1991;126(2):120-6. doi:10.2307/3577809
33. Sonneveld P, van Bekkum DW. The effect of whole-body irradiation on skeletal growth in rhesus monkeys. Radiology. Mar 1979;130(3):789-91. doi:10.1148/130.3.789
34. Zoetelief J, Wagemaker G, Broerse JJ. Dosimetry for total body irradiation of rhesus monkeys with 300 kV X-rays. Int J Radiat Biol. Aug 1998;74(2):265-72. doi:10.1080/095530098141654
35. Mattsson JL, Yochmowitz MG. Radiation-induced emesis in monkeys. Radiat Res. Apr 1980;82(1):191-9. doi:10.2307/3575247
36. Cockerham LG, Forcino CD. Effect of antihistamines, disodium cromoglycate (DSCG) or methysergide on post-irradiation cerebral blood flow and mean systemic arterial blood pressure in primates after 25 Gy, whole-body, gamma irradiation. J Radiat Res. Jun 1995;36(2):77-90. doi:10.1269/jrr.36.77
37. Hao J, Sun L, Huang H, et al. Effects of recombinant human interleukin 11 on thrombocytopenia and neutropenia in irradiated rhesus monkeys. Radiat Res. Aug 2004;162(2):157-63. 15387143. doi:10.1667/rr3202
38. Wood DH. Long-term mortality and cancer risk in irradiated rhesus monkeys. Radiat Res. May 1991;126(2):132-40. doi:10.2307/3577811
39. Niemer-Tucker MM, Sterk CC, de Wolff-Rouendaal D, et al. Late ophthalmological complications after total body irradiation in non-human primates. Int J Radiat Biol. Apr 1999;75(4):465-72. doi:10.1080/095530099140393
40. Zalusky R, Ghidoni JJ, McKinley J, Leffingwell TP, Melville GS. Leukemia in the rhesus monkey (Macaca mulata) exposed to whole-body neutron irradiation. Radiat Res. Jun 1965;25:410-6. doi:10.2307/3571981
41. Broerse JJ, van Bekkum DW, Hollander CF, Davids JA. Mortality of monkeys after exposure to fission neutrons and the effect of autologous bone marrow transplantation. Int J Radiat Biol Relat Stud Phys Chem Med. Sep 1978;34(3):253-64. doi:10.1080/09553007814550841
42. Franz CG. Effects of mixed neutron-gamma total-body irradiation on physical activity performance of rhesus monkeys. Radiat Res. Mar 1985;101(3):434-41. doi:10.2307/3576502
43. Kirk JH, Casey HW, Traynor JE. Summary of latent effects in long term survivors of whole body irradiations in primates. Life Sci Space Res. 1972;10:165-73. doi:10.1515/9783112480144-022
44. van Kleef EM, Zurcher C, Oussoren YG, et al. Long-term effects of total-body irradiation on the kidney of rhesus monkeys. Int J Radiat Biol. May 2000;76(5):641-8. doi:10.1080/095530000138303
45. Bakker B, Massa GG, van Rijn AM, et al. Effects of total-body irradiation on growth, thyroid and pituitary gland in rhesus monkeys. Radiother Oncol. May 1999;51(2):187-92. doi:10.1016/s0167-8140(99)00059-6
46. Stephens LC, King GK, Peters LJ, Ang KK, Schultheiss TE, Jardine JH. Acute and late radiation injury in rhesus monkey parotid glands. Evidence of interphase cell death. Am J Pathol. Sep 1986;124(3):469-78. doi:10.1016/S0167-8140(86)80096-2
47. Stephens LC, Ang KK, Schultheiss TE, King GK, Brock WA, Peters LJ. Target cell and mode of radiation injury in rhesus salivary glands. Radiother Oncol. Oct 1986;7(2):165-74. doi:10.1016/s0167-8140(86)80096-2
48. Dixon B. The biological and clinical effects of acute whole or partial body irradiation. J Soc Radiol Prot. 1985;5(3):121-8. doi:10.1088/0260-2814/5/3/003
49. Augustine AD, Gondre-Lewis T, McBride W, Miller L, Pellmar TC, Rockwell S. Animal models for radiation injury, protection and therapy. Radiat Res. Jul 2005;164(1):100-9. doi:10.1667/rr3388
50. Stone HB, Moulder JE, Coleman CN, et al. Models for evaluating agents intended for the prophylaxix, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003. Radiat Res. Dec 2004;162(6):711-728. doi:10.1667/rr3276
51. Dubois A, Nompleggi D, Castell DO. Histamine H2 receptor stimulation increases gastric emptying in monkeys. Am J Physiol. Dec 1988;255(6 Pt 1):G767-71. doi:10.1152/ajpgi.1988.255.6.G767
52. MacVittie TJ, Farese AM. Cytokine-based treatment of radiation injury: potential benefits after low-level radiation exposure. Mil Med. Feb 2002;167(2 Suppl):68-70.
53. Stickney DR, Dowding C, Garsd A, et al. 5-androstenediol stimulates multilineage hematopoiesis in rhesus monkeys with radiation-induced myelosuppression. Int Immunopharmacol. Nov 2006;6(11):1706-13. doi:10.1016/j.intimp.2006.07.005
54. Burdelya LG, Krivokrysenko VI, Tallant TC, et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. Apr 11 2008;320(5873):226-30. doi:10.1126/science.1154986
55. Darroudi F, Natarajan AT, Bentvelzen PA, et al. Detection of total- and partial-body irradiation in a monkey model: a comparative study of chromosomal aberration, micronucleus and premature chromosome condensation assays. Int J Radiat Biol. Aug 1998;74(2):207-15. doi:10.1080/095530098141582
56. 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. Jun 2001;77(6):703-12. doi:10.1080/09553000110043711
57. Blakely WF, Miller AC, Grace MB, et al. Radiation biodosimetry: applications for spaceflight. Adv Space Res. 2003;31(6):1487-93. doi:10.1016/s0273-1177(03)00085-1
58. Blakely WF, Miller AC, Grace MB, et al. Dose assessment based on molecular biomarkers. presented at: San Antionio, Texas Health Physics Society 36th Midyear Topical Meeting entitled "Radiation safety aspects of homeland security and emergency response" 2003; Alexandria, Virginia
59. Becciolini A, Giannardi G, Cionini L, Porciani S, Fallai C, Pirtoli L. Plasma amylase activity as a biochemical indicator of radiation injury to salivary glands. Acta Radiol Oncol. 1984;23(1):9-14. doi:10.3109/02841868409135978
60. Leslie MD, Dische S. Changes in serum and salivary amylase during radiotherapy for head and neck cancer: a comparison of conventionally fractionated radiotherapy with CHART. Radiother Oncol. May 1992;24(1):27-31. doi:10.1016/0167-8140(92)90350-4
61. Hofmann R, Schreiber GA, Willich N, Westhaus R, Bogl KW. Increased serum amylase in patients after radiotherapy as a probable bioindicator for radiation exposure. Strahlenther Onkol. Oct 1990;166(10):688-95.
62. Becciolini A, Porciani S, Lanini A, Balzi M, Faraoni P. Proposal for biochemical dosimeter for prolonged space flights. Phys Med. 2001;17 Suppl 1:185-6.
63. Akashi M, Hirama T, Tanosaki S, et al. Initial symptoms of acute radiation syndrome in the JCO criticality accident in Tokai-mura. J Radiat Res. Sep 2001;42 Suppl:S157-66. doi:10.1269/jrr.42.s157
64. Maier H, Bihl H. Effect of radioactive iodine therapy on parotid gland function. Acta Otolaryngol. Mar-Apr 1987;103(3-4):318-24. doi:10.3109/00016488709107290
65. Becciolini A, Porciani S, Lanini A, Benucci A, Castagnoli A, Pupi A. Serum amylase and tissue polypeptide antigen as biochemical indicator of salivary gland injury during iodine-131 therapy. Eur J Nucl Med. Oct 1994;21(10):1121-1125. doi:10.1007/bf00181068
66. Becciolini A, Porciani S, Lanini A. Marker determination for response monitoring: radiotherapy and disappearance curves. Int J Biol Markers. 1994;9(1):38-42. doi:10.1177/172460089400900108
67. Chen IW, Kereiakes JG, Silberstein EB, Aron BS, Saenger EL. Radiation-induced change in serum and urinary amylase levels in man. Radiat Res. Apr 1973;54(1):141-51. doi:10.2307/3573872
68. Dubray B, Girinski T, Thames HD, et al. Post-irradiation hyperamylasemia as a biological dosimeter. Radiother Oncol. May 1992;24(1):21-6. doi:10.1016/0167-8140(92)90349-y
69. Kashima HK, Kirkham WR, Andrews JR. Post-irradiation sialadenitis: a study of clinical features, histopathologic changes and serum enzyme variations following irradiation of human salivary glands. Am J Roentgenol. 1965;94:271-291.
70. Hennequin C, Cosset JM, Cailleux PE, et al. [Blood amylase: a biological marker in irradiation accidents? Preliminary results obtained at the Gustave-Roussy Institut (GRI) and a literature review]. Bull Cancer. 1989;76(6):617-24. L'amylasemie: un marqueur biologique des irradiations accidentelles? Resultats preliminaires obtenus a l'Institut Gustave-Roussy (IGR) et revue de la litterature.
71. Dainiak N. Hematologic consequences of exposure to ionizing radiation. Exp Hematol. Jun 2002;30(6):513-28. doi:10.1016/s0301-472x(02)00802-0
72. Fliedner TM, Friesecke L, Beyrer K. Medical management of radiation accidents –manual on the acute radiation syndrome. 2001. Available from: https://catalog.nlm.nih.gov/permalink/01NLM_INST/1o1phhn/alma9911303483406676
73. Graessle DH, Hofer EP, Lehn F, Fliedner TM. Classification of the individual medical severeness of radiation accidents within short time. presented at: The 10th Japanese-German Seminar, Nonlinear Problems in Dynamical Systems-Theory and applications; 2002; Noto Royal Hotel, Hakui, Ishikawa, Japan. Available from: https://scholar.google.com/scholar?q=Graessle+DH%2C+Hofer+EP%2C+Lehn+F%2C+Fliedner+TM.+Classification+of+the+individual+medical+severeness+of+radiation+accidents+within+short+time.+The+10th+Japanese-German+Seminar+on+Nonlinear+Problems+in+Dynamical+Systems%E2%80%94Theory+and+Applications%3B+September+30%E2%80%93October+3%2C+2002+at+the+Noto+Royal+Hotel%2C+Hakui%2C+Ishikawa%2C+Japan+%28unpublished+manuscript%29.
74. Zhang A, Azizova TV, Wald N, Day R. Changes of ratio of peripheral neutrophils and lymphocytes after radiation exposure may serve as a prognostic indicator of accident severity. presented at: Final program, 49th annual meeting of the Health Physics Society; 2004; McLean, Virginia.
75. Abend M, Blakely WF, Ostheim P, Schuele S, Port M. Early molecular markers for retrospective biodosimetry and prediction of acute health effects. J Radiol Prot. Jan 25 2022;42(1)(42) doi:10.1088/1361-6498/ac2434
76. Blakely WF, Port M, Ostheim P, Abend M. Radiation Research Society journal-based historical review of the use of biomarkers for radiation dose and injury assessment: acute health effects predictions. Radiat Res. Aug 1 2024;202(2):185-204. doi:10.1667/RADE-24-00121.1
77. Port M, Abend M. Clinical triage of radiation casualties-the hematological module of the Bundeswehr Institute of Radiobiology. Radiat Prot Dosimetry. Dec 1 2018;182(1):90-92. doi:10.1093/rpd/ncy141
78. Port M, Haupt J, Ostheim P, et al. Software tools for the evaluation of clinical signs and symptoms in the medical management of acute radiation syndrome-a five-year experience. Health Phys. Apr 1 2021;120(4):400-409. doi:10.1097/HP.0000000000001353
79. Sproull M, Kawai T, Krauze A, Shankavaram U, Camphausen K. Prediction of total-body and partial-body exposures to radiation using plasma proteomic expression profiles. Radiat Res. Dec 1 2022;198(6):573-581. doi:10.1667/RADE-22-00074.1
80. Sproull M, Fan Y, Chen Q, Meerzaman D, Camphausen K. Organ-specific biodosimetry modeling using proteomic biomarkers of radiation exposure. Radiat Res. Oct 1 2024;202(4):697-705. doi:10.1667/RADE-24-00092.1
81. Bolduc DL, Bunger R, Moroni M, Blakely WF. Modeling H-ARS using hematological parameters: a comparison between the non-human primate and minipig. Radiat Prot Dosimetry. Dec 2016;172(1-3):161-173. doi:10.1093/rpd/ncw159
82. Blakely WF, Bolduc DL, Debad J, et al. Use of proteomic and hematology biomarkers for prediction of hematopoietic acute radiation syndrome severity in baboon radiation models. Health Phys. Jul 2018;115(1):29-36. doi:10.1097/HP.0000000000000819
83. Port M, Herodin F, Drouet M, et al. Gene expression changes in irradiated baboons: a summary and interpretation of a decade of findings. Radiat Res. Jun 1 2021;195(6):501-521. doi:10.1667/RADE-20-00217.1
2. Waselenko JK, MacVittie TJ, Blakely WF, et al. Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Ann Intern Med. Jun 15 2004;140(12):1037-51. doi:10.7326/0003-4819-140-12-200406150-00015
3. Blakely WF, Salter CA, Prasanna PG. Early-response biological dosimetry--recommended countermeasure enhancements for mass-casualty radiological incidents and terrorism. Health Phys. Nov 2005;89(5):494-504. doi:10.1097/01.hp.0000175913.36594.a4
4. Goans RE, Waselenko JK. Medical management of radiological casualties. Health Phys. Nov 2005;89(5):505-12. doi:10.1097/01.hp.0000172144.94491.84
5. Swartz HM, Iwasaki A, Walczak T, et al. Measurements of clinically significant doses of ionizing radiation using non-invasive in vivo EPR spectroscopy of teeth in situ. Appl Radiat Isot. Feb 2005;62(2):293-9. doi:10.1016/j.apradiso.2004.08.016
6. National Council of Radiation Protection and Measurements. Measurement of persons accidentally contaminated with radionuclides. 1994. NCPR Report No 65. Available from: https://www.biblio.com/book/management-persons-accidentally-contaminated-radionuclides-recommendations/d/1045854443?srsltid=AfmBOoowq2iw28ZSA-lpZJ534sWt9rMJTb_GRMYeZmIqLbRNAyyjW0mm
7. National Council of Radiation Protection and Measurements. Management of terrorist events involving radioactive material. 2001. NCPR Report No 138. Available from: https://ncrponline.org/shop/reports/report-no-138-management-of-terrorist-events-involving-radioactive-material-2001/
8. National Council of Radiation Protection and Measurements. Key elements of preparing emergency responders for nuclear and radiological terrorism. 2005. NCRP Commentary No 19. Available from: https://ncrponline.org/shop/commentaries/commentary-no-19-key-elements-of-preparing-emergency-responders-for-nuclear-and-radiological-terrorism-2005/
9. Cohen KS. In: Gusev AE, Guskova AK, Mettler FA, Jr., eds. Medical management of radiation accidents. 2nd ed. CRC Press; 2001:chap Acute radiation sickness: underlying principles and assessment. Available from: https://www.taylorfrancis.com/chapters/mono/10.1201/9781420037197-10/acute-radiation-sickness-underlying-principles-assessment-kenneth-cohen-igor-gusev-angelina-guskova-fred-mettler
10. Blakely WF, Port M, Abend M. Early-response multiple-parameter biodosimetry and dosimetry: risk predictions. J Radiol Prot. Dec 6 2021;41(4)doi:10.1088/1361-6498/ac15df
11. Fliedner TM. Nuclear terrorism: the role of hematology in coping with its health consequences. Curr Opin Hematol. Nov 2006;13(6):436-44. doi:10.1097/01.moh.0000245696.77758.e6
12. Fliedner TM, Graessle D, Meineke V, Dorr H. Pathophysiological principles underlying the blood cell concentration responses used to assess the severity of effect after accidental whole-body radiation exposure: an essential basis for an evidence-based clinical triage. Exp Hematol. Apr 2007;35(4 Suppl 1):8-16. doi:10.1016/j.exphem.2007.01.006
13. Goans RE, Holloway EC, Berger ME, Ricks RC. Early dose assessment following severe radiation accidents. Health Phys. Apr 1997;72(4):513-8. doi:10.1097/00004032-199704000-00001
14. Goans RE, Holloway EC, Berger ME, Ricks RC. Early dose assessment in criticality accidents. Health Phys. Oct 2001;81(4):446-9. doi:10.1097/00004032-200110000-00009
15. Azizova TV, Osovets SV, Day RD, et al. Predictability of acute radiation injury severity. Health Phys. Mar 2008;94(3):255-63. doi:10.1097/01.HP.0000290833.66789.df
16. Blakely WF, Ossetrova NI, Mangalapus GL, et al. Amylase and blood cell-count hematological radiation-injury biomarkers in a rhesus monkey radiation model use of multiperameter and integrated biological dosimentry. Radiation Measurements. 2007;42(6-9):1164-1170. doi:10.1016/j.radmeas.2007.05.013
17. Blakely WF, Ossetrova NI, Whitnall MH, et al. Multiple parameter radiation injury assessment using a nonhuman primate radiation model-biodosimetry applications. Health Phys. Feb 2010;98(2):153-9. doi:10.1097/HP.0b013e3181b0306d
18. Nagy V, Parra NC, Shoemaker MO, Elliott TB, Ledney GD. Alanine dosimetry accurately determines radiation dose in nonhuman primates. Armed Forces Radiobiology Research Institute Special Publication. 2007:1-32.
19. Ossetrova NI, Blakely WF, Nagy V, et al. Non-human primate total-body irradiation model with limited and full medical supportive care including filgrastim for biodosimetry and injury assessment. Radiat Prot Dosimetry. Dec 2016;172(1-3):174-191. doi:10.1093/rpd/ncw176
20. Woods MJ, Collins SM. Half-life data-a critical review of TECDOC-619 update. Appl Radiat Isot. Feb-Apr 2004;60(2-4):257-62. doi:10.1016/j.apradiso.2003.11.026
21. International Standardization Organization and ASTM International. ISO/ASTM 51607:2004. Vol. 51607:2004(E). 2004. Standard practice for use of an alanine-EPR dosimetry system. Available from: https://www.iso.org/standard/39026.html
22. International Standardization Organization and ASTM International. ISO/ASTM 51607:2013. Vol. 51607:2013(E). 2013. Standard practice for use of an alanine-EPR dosimetry system. Available from: https://www.iso.org/standard/62955.html
23. Nagy V. Accuracy considerations in alanine dosimetry. Appl Radiat Isot. May 2000;52(5):1039-1050. doi:10.1016/S0969-8043(00)00052-X
24. Nagy V, Puhl JM, Desrosiers MF. Advancements in accuracy of the alanine dosimetry system. Part 2. The influence of the irradiation temperature. Radiat Phys Chem. 2000;57(1):1-9. doi:10.1016/S0969-806X(99)00339-4
25. Nagy V, Sleptchonok OF, Desrosiers MF, Weber RT, Heiss AH. Advancements in accuracy of the alanine EPR dosimetry system. Part III: Usefulness of an adjacent reference sample. Appl Radiat Isot. 2000;59(4):429-441. doi:10.1016/S0969-806X(00)00275-9
26. National Research Council. Guide for the care and use of laboratory animals. 8th ed. National Academies Press; 2011.
27. Weatherall D, Working Group. The use of non-human primates in research. 2006:149. A working group report chaired by Sir David Weatherall FMedSci. 2006. Available from: https://acmedsci.ac.uk/file-download/34945-1165861003.pdf
28. King GL, Sandgren DJ, Mitchell JM, Bolduc DL, Blakely WF. System for scoring severity of acute radiation syndrome response in rhesus macaques (Macaca mulatta). Comp Med. Dec 1 2018;68(6):474-488. doi:10.30802/AALAS-CM-17-000106
29. Nagy V, Desrosiers MF. Complex time dependence of the EPR signal of irradiated L-α-alanine. Appl Radiat Isot. 1996;47(8):789-793. doi:10.1016/0969-8043(96)00053-X
30. Shleien B, Slaback LA, Jr., Birky BK. Handbook of health physics and radiological health. 3rd ed. Williams & Wilkins; 1998. Available from: https://books.google.com/books/about/Handbook_of_Health_Physics_and_Radiologi.html?id=j2vGQgAACAAJ
31. Fanton JW, Golden JG. Radiation-induced endometriosis in Macaca mulatta. Radiat Res. May 1991;126(2):141-6. doi:10.2307/3577812
32. Hardy KA. Dosimetry methods used in the studies of the effects of protons on primates: a review. Radiat Res. May 1991;126(2):120-6. doi:10.2307/3577809
33. Sonneveld P, van Bekkum DW. The effect of whole-body irradiation on skeletal growth in rhesus monkeys. Radiology. Mar 1979;130(3):789-91. doi:10.1148/130.3.789
34. Zoetelief J, Wagemaker G, Broerse JJ. Dosimetry for total body irradiation of rhesus monkeys with 300 kV X-rays. Int J Radiat Biol. Aug 1998;74(2):265-72. doi:10.1080/095530098141654
35. Mattsson JL, Yochmowitz MG. Radiation-induced emesis in monkeys. Radiat Res. Apr 1980;82(1):191-9. doi:10.2307/3575247
36. Cockerham LG, Forcino CD. Effect of antihistamines, disodium cromoglycate (DSCG) or methysergide on post-irradiation cerebral blood flow and mean systemic arterial blood pressure in primates after 25 Gy, whole-body, gamma irradiation. J Radiat Res. Jun 1995;36(2):77-90. doi:10.1269/jrr.36.77
37. Hao J, Sun L, Huang H, et al. Effects of recombinant human interleukin 11 on thrombocytopenia and neutropenia in irradiated rhesus monkeys. Radiat Res. Aug 2004;162(2):157-63. 15387143. doi:10.1667/rr3202
38. Wood DH. Long-term mortality and cancer risk in irradiated rhesus monkeys. Radiat Res. May 1991;126(2):132-40. doi:10.2307/3577811
39. Niemer-Tucker MM, Sterk CC, de Wolff-Rouendaal D, et al. Late ophthalmological complications after total body irradiation in non-human primates. Int J Radiat Biol. Apr 1999;75(4):465-72. doi:10.1080/095530099140393
40. Zalusky R, Ghidoni JJ, McKinley J, Leffingwell TP, Melville GS. Leukemia in the rhesus monkey (Macaca mulata) exposed to whole-body neutron irradiation. Radiat Res. Jun 1965;25:410-6. doi:10.2307/3571981
41. Broerse JJ, van Bekkum DW, Hollander CF, Davids JA. Mortality of monkeys after exposure to fission neutrons and the effect of autologous bone marrow transplantation. Int J Radiat Biol Relat Stud Phys Chem Med. Sep 1978;34(3):253-64. doi:10.1080/09553007814550841
42. Franz CG. Effects of mixed neutron-gamma total-body irradiation on physical activity performance of rhesus monkeys. Radiat Res. Mar 1985;101(3):434-41. doi:10.2307/3576502
43. Kirk JH, Casey HW, Traynor JE. Summary of latent effects in long term survivors of whole body irradiations in primates. Life Sci Space Res. 1972;10:165-73. doi:10.1515/9783112480144-022
44. van Kleef EM, Zurcher C, Oussoren YG, et al. Long-term effects of total-body irradiation on the kidney of rhesus monkeys. Int J Radiat Biol. May 2000;76(5):641-8. doi:10.1080/095530000138303
45. Bakker B, Massa GG, van Rijn AM, et al. Effects of total-body irradiation on growth, thyroid and pituitary gland in rhesus monkeys. Radiother Oncol. May 1999;51(2):187-92. doi:10.1016/s0167-8140(99)00059-6
46. Stephens LC, King GK, Peters LJ, Ang KK, Schultheiss TE, Jardine JH. Acute and late radiation injury in rhesus monkey parotid glands. Evidence of interphase cell death. Am J Pathol. Sep 1986;124(3):469-78. doi:10.1016/S0167-8140(86)80096-2
47. Stephens LC, Ang KK, Schultheiss TE, King GK, Brock WA, Peters LJ. Target cell and mode of radiation injury in rhesus salivary glands. Radiother Oncol. Oct 1986;7(2):165-74. doi:10.1016/s0167-8140(86)80096-2
48. Dixon B. The biological and clinical effects of acute whole or partial body irradiation. J Soc Radiol Prot. 1985;5(3):121-8. doi:10.1088/0260-2814/5/3/003
49. Augustine AD, Gondre-Lewis T, McBride W, Miller L, Pellmar TC, Rockwell S. Animal models for radiation injury, protection and therapy. Radiat Res. Jul 2005;164(1):100-9. doi:10.1667/rr3388
50. Stone HB, Moulder JE, Coleman CN, et al. Models for evaluating agents intended for the prophylaxix, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003. Radiat Res. Dec 2004;162(6):711-728. doi:10.1667/rr3276
51. Dubois A, Nompleggi D, Castell DO. Histamine H2 receptor stimulation increases gastric emptying in monkeys. Am J Physiol. Dec 1988;255(6 Pt 1):G767-71. doi:10.1152/ajpgi.1988.255.6.G767
52. MacVittie TJ, Farese AM. Cytokine-based treatment of radiation injury: potential benefits after low-level radiation exposure. Mil Med. Feb 2002;167(2 Suppl):68-70.
53. Stickney DR, Dowding C, Garsd A, et al. 5-androstenediol stimulates multilineage hematopoiesis in rhesus monkeys with radiation-induced myelosuppression. Int Immunopharmacol. Nov 2006;6(11):1706-13. doi:10.1016/j.intimp.2006.07.005
54. Burdelya LG, Krivokrysenko VI, Tallant TC, et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science. Apr 11 2008;320(5873):226-30. doi:10.1126/science.1154986
55. Darroudi F, Natarajan AT, Bentvelzen PA, et al. Detection of total- and partial-body irradiation in a monkey model: a comparative study of chromosomal aberration, micronucleus and premature chromosome condensation assays. Int J Radiat Biol. Aug 1998;74(2):207-15. doi:10.1080/095530098141582
56. 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. Jun 2001;77(6):703-12. doi:10.1080/09553000110043711
57. Blakely WF, Miller AC, Grace MB, et al. Radiation biodosimetry: applications for spaceflight. Adv Space Res. 2003;31(6):1487-93. doi:10.1016/s0273-1177(03)00085-1
58. Blakely WF, Miller AC, Grace MB, et al. Dose assessment based on molecular biomarkers. presented at: San Antionio, Texas Health Physics Society 36th Midyear Topical Meeting entitled "Radiation safety aspects of homeland security and emergency response" 2003; Alexandria, Virginia
59. Becciolini A, Giannardi G, Cionini L, Porciani S, Fallai C, Pirtoli L. Plasma amylase activity as a biochemical indicator of radiation injury to salivary glands. Acta Radiol Oncol. 1984;23(1):9-14. doi:10.3109/02841868409135978
60. Leslie MD, Dische S. Changes in serum and salivary amylase during radiotherapy for head and neck cancer: a comparison of conventionally fractionated radiotherapy with CHART. Radiother Oncol. May 1992;24(1):27-31. doi:10.1016/0167-8140(92)90350-4
61. Hofmann R, Schreiber GA, Willich N, Westhaus R, Bogl KW. Increased serum amylase in patients after radiotherapy as a probable bioindicator for radiation exposure. Strahlenther Onkol. Oct 1990;166(10):688-95.
62. Becciolini A, Porciani S, Lanini A, Balzi M, Faraoni P. Proposal for biochemical dosimeter for prolonged space flights. Phys Med. 2001;17 Suppl 1:185-6.
63. Akashi M, Hirama T, Tanosaki S, et al. Initial symptoms of acute radiation syndrome in the JCO criticality accident in Tokai-mura. J Radiat Res. Sep 2001;42 Suppl:S157-66. doi:10.1269/jrr.42.s157
64. Maier H, Bihl H. Effect of radioactive iodine therapy on parotid gland function. Acta Otolaryngol. Mar-Apr 1987;103(3-4):318-24. doi:10.3109/00016488709107290
65. Becciolini A, Porciani S, Lanini A, Benucci A, Castagnoli A, Pupi A. Serum amylase and tissue polypeptide antigen as biochemical indicator of salivary gland injury during iodine-131 therapy. Eur J Nucl Med. Oct 1994;21(10):1121-1125. doi:10.1007/bf00181068
66. Becciolini A, Porciani S, Lanini A. Marker determination for response monitoring: radiotherapy and disappearance curves. Int J Biol Markers. 1994;9(1):38-42. doi:10.1177/172460089400900108
67. Chen IW, Kereiakes JG, Silberstein EB, Aron BS, Saenger EL. Radiation-induced change in serum and urinary amylase levels in man. Radiat Res. Apr 1973;54(1):141-51. doi:10.2307/3573872
68. Dubray B, Girinski T, Thames HD, et al. Post-irradiation hyperamylasemia as a biological dosimeter. Radiother Oncol. May 1992;24(1):21-6. doi:10.1016/0167-8140(92)90349-y
69. Kashima HK, Kirkham WR, Andrews JR. Post-irradiation sialadenitis: a study of clinical features, histopathologic changes and serum enzyme variations following irradiation of human salivary glands. Am J Roentgenol. 1965;94:271-291.
70. Hennequin C, Cosset JM, Cailleux PE, et al. [Blood amylase: a biological marker in irradiation accidents? Preliminary results obtained at the Gustave-Roussy Institut (GRI) and a literature review]. Bull Cancer. 1989;76(6):617-24. L'amylasemie: un marqueur biologique des irradiations accidentelles? Resultats preliminaires obtenus a l'Institut Gustave-Roussy (IGR) et revue de la litterature.
71. Dainiak N. Hematologic consequences of exposure to ionizing radiation. Exp Hematol. Jun 2002;30(6):513-28. doi:10.1016/s0301-472x(02)00802-0
72. Fliedner TM, Friesecke L, Beyrer K. Medical management of radiation accidents –manual on the acute radiation syndrome. 2001. Available from: https://catalog.nlm.nih.gov/permalink/01NLM_INST/1o1phhn/alma9911303483406676
73. Graessle DH, Hofer EP, Lehn F, Fliedner TM. Classification of the individual medical severeness of radiation accidents within short time. presented at: The 10th Japanese-German Seminar, Nonlinear Problems in Dynamical Systems-Theory and applications; 2002; Noto Royal Hotel, Hakui, Ishikawa, Japan. Available from: https://scholar.google.com/scholar?q=Graessle+DH%2C+Hofer+EP%2C+Lehn+F%2C+Fliedner+TM.+Classification+of+the+individual+medical+severeness+of+radiation+accidents+within+short+time.+The+10th+Japanese-German+Seminar+on+Nonlinear+Problems+in+Dynamical+Systems%E2%80%94Theory+and+Applications%3B+September+30%E2%80%93October+3%2C+2002+at+the+Noto+Royal+Hotel%2C+Hakui%2C+Ishikawa%2C+Japan+%28unpublished+manuscript%29.
74. Zhang A, Azizova TV, Wald N, Day R. Changes of ratio of peripheral neutrophils and lymphocytes after radiation exposure may serve as a prognostic indicator of accident severity. presented at: Final program, 49th annual meeting of the Health Physics Society; 2004; McLean, Virginia.
75. Abend M, Blakely WF, Ostheim P, Schuele S, Port M. Early molecular markers for retrospective biodosimetry and prediction of acute health effects. J Radiol Prot. Jan 25 2022;42(1)(42) doi:10.1088/1361-6498/ac2434
76. Blakely WF, Port M, Ostheim P, Abend M. Radiation Research Society journal-based historical review of the use of biomarkers for radiation dose and injury assessment: acute health effects predictions. Radiat Res. Aug 1 2024;202(2):185-204. doi:10.1667/RADE-24-00121.1
77. Port M, Abend M. Clinical triage of radiation casualties-the hematological module of the Bundeswehr Institute of Radiobiology. Radiat Prot Dosimetry. Dec 1 2018;182(1):90-92. doi:10.1093/rpd/ncy141
78. Port M, Haupt J, Ostheim P, et al. Software tools for the evaluation of clinical signs and symptoms in the medical management of acute radiation syndrome-a five-year experience. Health Phys. Apr 1 2021;120(4):400-409. doi:10.1097/HP.0000000000001353
79. Sproull M, Kawai T, Krauze A, Shankavaram U, Camphausen K. Prediction of total-body and partial-body exposures to radiation using plasma proteomic expression profiles. Radiat Res. Dec 1 2022;198(6):573-581. doi:10.1667/RADE-22-00074.1
80. Sproull M, Fan Y, Chen Q, Meerzaman D, Camphausen K. Organ-specific biodosimetry modeling using proteomic biomarkers of radiation exposure. Radiat Res. Oct 1 2024;202(4):697-705. doi:10.1667/RADE-24-00092.1
81. Bolduc DL, Bunger R, Moroni M, Blakely WF. Modeling H-ARS using hematological parameters: a comparison between the non-human primate and minipig. Radiat Prot Dosimetry. Dec 2016;172(1-3):161-173. doi:10.1093/rpd/ncw159
82. Blakely WF, Bolduc DL, Debad J, et al. Use of proteomic and hematology biomarkers for prediction of hematopoietic acute radiation syndrome severity in baboon radiation models. Health Phys. Jul 2018;115(1):29-36. doi:10.1097/HP.0000000000000819
83. Port M, Herodin F, Drouet M, et al. Gene expression changes in irradiated baboons: a summary and interpretation of a decade of findings. Radiat Res. Jun 1 2021;195(6):501-521. doi:10.1667/RADE-20-00217.1