Linking the Human Response to Unplanned Radiation and Treatment to the Nonhuman Primate Response to Controlled Radiation and Treatment

Abstract

A key difficulty in developing countermeasures against radiation-induced health impairments is the clear lack of controlled clinical studies, due to the relatively low number of radiation victims worldwide. Instead, established and accepted animal models, as well as the recommendations of national and international expert panels and committees, are the main sources of information. Therefore, the development of countermeasures requires comparison of data from many sources and accumulation of information consistent with the U. S. Food and Drug Administration's “Animal Rule.” A new approach is the comparative analysis of human data from the SEARCH (System for Evaluation and Archiving of Radiation Accidents based on Case Histories) database and data from non-human primate (NHP) animal model studies. The SEARCH database contains 824 clinical cases from 81 radiation accidents in 19 countries. This exceptional collection of clinical data from accidentally radiation exposed persons is analysed regarding clinical signs and symptoms of radiation induced health impairments. To analyze the time course of radiation syndromes, clinical parameters common to the SEARCH and NHP databases have to be assigned into comparable categories of clinical severity for each species. The goal is to establish a method for comparison of human and NHP data, to validate the NHP data as a surrogate for human efficacy/clinical studies and opening a way for the extraction of diagnostic and treatment methods for humans after radiation exposure according to relevant regulations.

The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates

“…Study groups were composed of approximately equal numbers of male and female animals. Following irradiation, animals generally developed a clinical picture of ARS with typical prodromal and manifest illness features [ 31 , 39 ].…”

“…Instead (in addition to safety trials in humans) such therapeutics are evaluated for efficacy in two animal species in which the model of the disease of interest as well as the response to the drug of interest closely model those in humans. Therefore, experiments in non-human primate (NHP) model of ARS that closely resembles human ARS [ 31 ] are considered obligatory. Here, we summarize the data on the radiomitigative efficacy of entolimod obtained in a series of exploratory studies performed in 164 NHPs.…”

Differential Mobility Spectrometry-Mass Spectrometry (DMS-MS) in Radiation Biodosimetry: Rapid and High-Throughput Quantitation of Multiple Radiation Biomarkers in Nonhuman Primate Urine

“…Mortality rate also has a dependence on the level of supportive treatment provided [51]. Similar human response occurs at doses which are lower by a factor of 1.5–2.0 [55, 56]. …”

Lipidomic dysregulation within the lung parenchyma following whole-thorax lung irradiation: Markers of injury, inflammation and fibrosis detected by MALDI-MSI

“…Our research consortium, the Medical Countermeasures Against Radiological Threats (MCART), has developed animal models that mimic the dose- and time-dependent latency, incidence, severity and progression of radiation-induced injury, spanning the multi-organ syndromes observed as a consequence of TBI, PBI and whole-thorax lung irradiation (WTLI) 2 , 6 – 9 , 22 – 24 . Animal models are vital for the development and approval of MCM under the FDA “animal rule” (FDA-AR), which requires the use of well-defined animal models for the approval of new drugs when human efficacy studies cannot be carried out 24 .…”