Development of the Göttingen Minipig Model: GB and GF Toxicity

Abstract

The dwindling availability of nonhuman primates (NHP) and increased ethical concerns over their use as experimental animals has driven a search for alternative animal models that can predict the effects of organophosphorus nerve agent (OPNA) in humans and to develop better medical countermeasures (MCM). Göttingen minipigs are physiologically and anatomically similar to humans, and are being considered as a potential alternative species for OPNA and MCM research. In the current study, fifteen sexually mature male Göttingen minipigs were utilized to determine the intramuscular (IM) 24‐hour median lethal dose (LD50) for the nerve agent sarin (GB) and cyclosarin (GF) using an up‐and‐down dose selection method. The initial doses for GB and GF were selected by approximating established lethality data for VX in Göttingen minipigs across IM and subcutaneous (SC) routes of administration. All animals exhibited typical signs of nerve agent poisoning immediately after being exposed to GB/GF. Three unique doses were required to estimate a GB LD50 of 40.00 µg/kg (95% confidence interval 33.25 µg/kg ‐ 49.76 µg/kg) and a GF LD50 of 40.57 µg/kg (95% confidence interval 33.03 µg/kg ‐ 49.73 µg/kg) with maximum likelihood estimation. The progression of toxic signs and the LD50 estimates obtained support the further development and use of Göttingen minipigs as a model to study MCMs and OPNAs.