The Gastrointestinal Subsyndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose-response Relationship With and Without Medical Management

Autor: Ann M. Farese, Catherine Booth, Christopher S Potten, George A. Parker, Thomas J. MacVittie, Kim G. Hankey, Gregory Tudor, William E. Jackson
Rok vydání: 2019
Předmět:
Zdroj: Health Phys
ISSN: 1538-5159
0017-9078
DOI: 10.1097/hp.0000000000000903
Popis: Well-characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the Food and Drug Administration “animal rule”. Development of a model for the acute GI-ARS requires knowledge of the radiation dose response relationship and time course of mortality and morbidity across the acute and prolonged gastrointestinal radiation syndrome. The nonhuman primate, Rhesus macaque, is a relevant animal model that has been used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality relative to the H-, GI-ARS and lung injury. It can be used to assess the natural history of GI damage, concurrent multiple organ injury and aspects of the mechanism of action for acute radiation exposure and treatment. A systematic review of relevant studies that determined the dose response relationship for the gastrointestinal acute and prolonged radiation syndrome in the Rhesus macaque relative to radiation dose, quality, dose rate, exposure uniformity and use of medical management has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present and US HHS REPORT (2002 to present). The following terms were used: Rhesus, total-body irradiation, total-body x-irradiation, TBI, irradiation, gamma radiation, gastrointestinal system, LD50, LD50/60, hematopoietic radiation syndrome, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, gastrointestinal radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,923. Thirty-two (32) studies, utilizing 1,364 total nonhuman primates (NHP), Rhesus Macaca mulatta, were evaluated to provide an informative and consistent review. Ten (10) primary studies provided adequate data to establish dose response relationships (DRR)s for the acute GI-ARS. The DRRs were determined for uniform or non-uniform total-body irradiation (TBI) with 240–250kVp or 2Mev x-radiation, Co-60 gamma radiation, isotope-derived gamma-radiation, reactor- and nuclear weapon-derived mixed gamma:neutron radiation and 6MV LINAC-derived photons delivered at various dose rates from a total-body, bilateral, rotational or unilateral exposure aspect in the absence or presence of medical management. The DRRs established by a probit analysis versus linear dose relationship were characterized by two main parameters or dependent variables, a slope and LD50/15. Respective LD50/15 values for the primary studies without use of medical management that used 250kVp x-radiation (three studies, total n=234), 2Mev x-radiation (n=84) and Co-60 gamma-radiation (n=90) were: 250kVp x-radiation (605rad [572, 636], 581rad [542, 621], and 608rad [369, 871]); Co-60 gamma -radiation (708rad [683, 736]) and 2Mev x-radiation (671rad [632, 715]). The respective slopes were steep and ranged from 0.402 to 1.915 probits per linear dose. The DRR, LD50/15 value and slope were also determined for total-body, non-uniform, unilateral, pulse-rate exposure to reactor-derived mixed gamma:neutron radiation (total n=111). The LD50/15 value was 482rad with a slope of 0.992 [0.142, 1.99]. Two contemporary studies provided DRRs for NHP exposed to TBI or PBI with 5% bone marrow sparing (PBI/BM5) with 6 MV LINAC-derived photons with administration of medical management. The LD50/15 and slopes were: TBI, 11.33 Gy [10.81, 11.75] with a slope of 0.917 [0.701, 1.133]; PBI/BM5, 12.01 Gy [11.71, 12.52] with a slope of 1.001 [0.599, 1.415]. The PBI/BM5 model also provided a modified, longitudinal, image-based histopathology of damage to the small intestine through 180d post exposure relative to normal, un-irradiated age-matched tissue. Secondary studies (12) provided data sets of appropriate limited studies that did not describe a DRR for the GI-ARS but included adequate control data sets or a range of mortality values from high-dose range exposure in the conduct of establishing the DRR for the H-ARS, were used to support the threshold and mid- to high-lethal dose range for the GI-ARS. Tertiary studies (12) provided data sets that supported the incidence, time course, severity, histology, physiology and biomarkers of radiation-induced GI injury in the NHP. The acute GI-ARS and prolonged GI injury were evaluated at threshold doses to include initial concomitant GI injury consequent to TBI at mid- to high-dose lethal H-ARS. The available evidence provided a relatively consistent and reliable data base that characterized the DRR and survival probability over the 15 day time course for the acute GI-ARS in young Rhesus macaques exposed to total-body and partial-body irradiation with several sources of differing radiation quality, dose rate and non-uniform exposure with and without medical management. The GI-ARS occurred with concomitant evolution of the H-ARS. The image-based histopathology provided a clear demonstration of the pronounced radiation-induced damage to the GI system along the longitudinal course from acute to prolonged damage through the 180d study duration. The DRRs for the GI-ARS are characterized by steep slopes and relative LD50/15 values that reflected the biological effect of radiation quality, exposure aspect, dose rate and medical management over a range in time from 1954–2015.
Databáze: OpenAIRE
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