Effects of Solar Particle Event Proton Radiation on Parameters Related to Ferret Emesis

Abstract

The effectiveness of simulated solar particle event (SPE) proton radiation to induce retching and vomiting was evaluated in the ferret experimental animal model. The endpoints measured in the study included: (1) the fraction of animals that retched or vomited, (2) the number of retches or vomits observed, (3) the latency period before the first retch or vomit and (4) the duration between the first and last retching or vomiting events. The results demonstrated that γ ray and proton irradiation delivered at a high dose rate of 0.5 Gy/min induced dose-dependent changes in the endpoints related to retching and vomiting. The minimum radiation doses required to induce statistically significant changes in retching- and vomiting-related endpoints were 0.75 and 1.0 Gy, respectively, and the relative biological effectiveness (RBE) of proton radiation at the high dose rate did not significantly differ from 1. Similar but less consistent and smaller changes in the retching- and vomiting-related endpoints were observed for groups irradiated with γ rays and protons delivered at a low dose rate of 0.5 Gy/h. Since this low dose rate is similar to a radiation dose rate expected during a SPE, these results suggest that the risk of SPE radiation-induced vomiting is low and may reach statistical significance only when the radiation dose reaches 1 Gy or higher.

Biological effects of space radiation and development of effective countermeasures

“…High LET 56 Fe particles and fission neutrons were comparable in their ability to produce emetic responses (retching or vomiting) in ferrets with an ED 50 of 0.35 Gy and 0.40 Gy, respectively (195), whereas γ-rays were shown to be intermediately effective with an ED 50 of 0.77 Gy (122) to 0.95 Gy (195), and high energy electrons were the least effective, with an ED 50 of 1.38 Gy (195). The ED 10 , ED 50 and ED 90 values estimated for the fraction of animals that vomited after proton irradiation at the HDR were comparable to the ED 10 , ED 50 and ED 90 values after γ-ray irradiation at the high dose rate in our study (194) or at a dose-rate of 1 Gy/minute, as reported previously (122). The ED 10 and ED 50 , but not the ED 90 , values estimated for the fraction of animals that retched (or vomited) post- irradiation with protons at the HDR were lower than the lower limits of the respective 95% confidence intervals previously reported for γ-rays (122), suggesting that HDR proton irradiation was more effective than HDR γ-ray irradiation in inducing retching and vomiting.…”

“…In our studies performed with female descented Fitch ferrets aged 12 to 16 weeks, irradiation with 60 Co γ-rays or 155-MeV protons at a high dose rate of 0.5 Gy/minute resulted in dose-dependent changes in the endpoints related to retching and vomiting, such as the fraction of animals that retched or vomited, the number of retching and vomiting events, the length of the latency period leading to the first retching or vomiting event and the duration between the first and last retching or vomiting events (194). A dose-response relationship was observed for ferret vomiting and retching at the high dose rate.…”

Dose- and ApoE Isoform-Dependent Cognitive Injury after Cranial56Fe Irradiation in Female Mice

“…These doses are at the high end of those estimated for the largest SPEs for an astronaut in a minimally shielded environment and prompted investigation of emesis in a non-rodent animal model, as mice and rats do not vomit. In a study by Sanzari et al (2013), 12-16-week-old female Fitch ferrets were whole-body-irradiated with 0.25 to 2 Gy of 60 Co γ-rays or spread out Bragg peak protons from a 155 MeV beam (to simulate the SPE spectrum) at 0.5 Gy/min or 0.5 Gy/hr and followed for up to 7 hours for retching-and vomitingrelated endpoints. The high-dose-rate cohort exhibited ED 50 (95% CI) values of 0.48 (0.16-0.81), 1.01 (0.91-1.12), and 0.89 (0.69-1.08) Gy for retching after protons and vomiting after gamma rays or protons, respectively.…”

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

“…Another advantage of using ferrets as an animal model for radiation-induced vomiting is that the prodromal response appears at lower doses and with an earlier onset time as compared to other species. The effective dose at which 50% of ferrets exhibited an emetic response to radiation is similar to that of humans (Sanzari et al 2013). Data from the ferret studies have been used to develop a mathematical model for the human emetic response to radiation as well as to identify the dopaminergic mechanisms that play a minor role in radiation-induced emesis in the ferret (Benson et al 2008).…”

“…Rodent (mice), canine, and NHP models are used most frequently for the development of radiation countermeasures and studying the injuries caused by radiation exposure. Some studies have used additional animal models such as rats, guinea pigs, rabbits, ferrets, and minipigs to study the effects of radiation exposure for the development of selected radiation countermeasures (Martin et al 1998;King et al 1999;Augustine et al 2005;Williams et al 2010Williams et al , 2012Sanzari et al 2013;Krigsfeld et al 2014a;Shim et al 2014). …”