System for Scoring Severity of Acute Radiation Syndrome Response in Rhesus Macaques (Macaca mulatta)

Abstract

The currently accepted scheme to assess humans exposed to life-threatening radiation doses is the MEdical TREatment ProtocOLs for Radiation Accident Victims (METREPOL). ME-TREPOL is used to evaluate the time course and severity of radiation injury from acute radiation syndrome (ARS) on the basis of relevant organ-based systems to provide medical management guidance. 26 The METREPOL system is consistent with some of the pioneering work on radiation-induced clinical signs and symptoms. 3,31-33 More recently, METROPOL has been updated for use in a 6-page Armed Forces Radiobiology Research Institute Biodosimetry Worksheet. 65,66 The first verification of the effectiveness of the clinical dosimetry system METREPOL to rapidly and accurately predict later occurring ARS severity and to develop medical management strategies were based on real clinical data from case histories of accidentally exposed patients. 21 Individual assessment of ARS severity response will allow medical responders to better manage irradiation-accident victims consistent with recommended guidelines. 34 Significant gaps exist to enhance radiologic medical countermeasures and biodosimetry capabilities in response to radiologic threats. One major gap is the ability to rapidly identify persons exposed to potentially life-threatening radiation doses and distinguish them from those not exposed or exposed to lower doses. 12 Biodosimetry devices for this purpose should be useful for triage applications involving mass-casualty exposure incidents and must obtain the necessary approvals by governmental regulatory agencies (that is, FDA). 1 Approval by appropriate regulatory agencies for the use of medical radiologic countermeasure drugs involves demonstration of safety and efficacy, ideally in humans. When human data are inaccessible, relevant animal models should be used. No biodosimetry devices are currently approved by the FDA, and approaches to obtain approval for candidate devices will likely be based on initial studies using small rodent models to supplement results from human patients undergoing radiation therapy for cancer and from limited radiation accidents. 42 Because human data are quite sparse, a relevant nonrodent animal model-one that permits characterization of complete doseand time-course responses-is needed for biodosimetry device validation. NHP provide the bridge in scientific research from small laboratory rodents to humans for medical countermeasure and biodosimetry studies.

Nuclear and Radiological Emergencies: Biological Effects, Countermeasures and Biodosimetry

“…ARS involves different phases of biological injury that may follow exposure (of the whole body or its majority) to a high dose of radiation (ordinarily in a brief timeframe). Its seriousness relies upon the radiation dose and normally includes syndromes whose term is directly correlated with the total dose received (and, ultimately, with the pace of exposure) [ 61 , 62 , 63 , 64 ]. Initially, a prodromal phase may show up with side effects, for example, sickness, spewing, and torpidity.…”

Longitudinal multi-omic changes in the transcriptome and proteome of peripheral blood cells after a 4 Gy total body radiation dose to Rhesus macaques

“…2 , 3 and 4 ). A comparison of CBC absolute counts with a scoring system based on the human METREPOL action [ 5 , 46 ] but modified for NHP, showed that the 4 Gy TBI effect was between mild (score 1, based on hemoglobin levels at > 20 days between 80–109 g/dL and HCT (hematocrit) > 20 days between 0.27–0.32%) and moderate (score 2, based on platelet levels at > 8 days at < 180 X 10 9 /L, neutrophil levels between 10 – 21 days at < 1.2 X 10 9 /L and lymphocyte levels between 1 -14 days at 0.45-1 X 10 9 /L, see Supplementary table 2 ) [ 36 ]. Comparison of cell count recovery trends with Rhesus macaques exposed to 6 Gy TBI were comparable, with neutropenia and lymphopenia resolving within 30 days [ 47 ].…”

“…The objective of the current study was to identify and compare the induction and persistence of different radiation -omics and cytogenetic responses in NHP peripheral blood in vivo after a 4 Gy TBI exposure. We also compared complete blood cell counts (CBC) with Acute Radiation Syndrome (ARS) severity scores as reported in King et al, which are METREPOL (MEdical TREatment ProtocOLs for Radiation Accident Victims) human scores modified for H-ARS in NHP [ 5 , 36 , 37 ]. We used network analysis to connect multi-level information from mRNA and proteins in the time series and also report long-term cytogenetic DNA damage effects and recovery.…”

Dose-Dependent Testicular Injury and Recovery after Total-Body Irradiation in Rhesus Monkeys

“…Animals were routinely screened three times a year with clinical exams, complete blood counts, and serum chemistry panels. Signs of hematologic failure or infection were monitored using the methods of Uckun, as modified from the Children's Cancer Group Clinical Toxicity Criteria ( 17 ).…”