, 2011), increasing the relevance of these results. The great majority of previous research studies for investigation AZD6244 of OP antidotes have been done in rodents. These studies have limited relevance to acute human toxicity as seen in self-poisoning: rodents metabolize xenobiotics differently to humans (Martignoni et al., 2006 and Tang et al., 2001). In addition, the OP compound has usually been given by an irrelevant route (e.g. intravenous), as an unformulated AI, and the rodent has not been treated with supportive care (ventilation, vasopressors) as occurs for humans. Our model is more relevant to human poisoning, with the pesticide given by the correct route and formulation to a species that has

physiological and biochemical similarities to human, receiving typical supportive care. This relevance is apparent in the similarity of the poisoning seen in these minipigs and poisoned humans, with the same clinical syndrome, AChE inhibition,

and response to pralidoxime (Davies et al., 2008 and Eddleston et al., 2005). Although in vitro Selleck MLN0128 studies indicate that pig AChE inhibited by highly toxic OP nerve agents is less well activated by oximes than similarly inhibited human AChE (Aurbek et al., 2006 and Worek et al., 2008), this is moot here since human AChE is not reactivated by pralidoxime – the same situation as we found in our pig model. Use of such a model in future animal studies will reduce the number of animals used (3Rs). Due to welfare issues, the animals were anaesthetised with isoflurane for the study. Although the use of anaesthesia is another limitation, all arms of the study had identical anaesthesia and this could not explain the differences seen. Isoflurane anaesthesia was selected since it has a consistent and mild (about 10%) inhibitory effect

on AChE activity (Dorandeu et al., 2007). The animals were anaesthetised for about 1.5 h before poison administration. Differences between arms of the study were apparent within 30 min, making it unlikely in this time frame that induction of CYP enzymes involved in the metabolism of OPs could be involved in Carnitine palmitoyltransferase II the differences seen. In conclusion, this study indicates that dimethoate AI is not solely responsible for toxicity in the pig. Instead, coformulants are an important element of OP toxicity; therefore their toxicity should be considered by manufacturers, regulators and clinicians. Further studies are required to determine the generality of this finding and how formulations can be changed to improve human safety without reducing agricultural efficacy. ME designed the study, established the minipig model, performed the studies and analysis, and wrote the first draft with input from all authors. JMS, IS, TK, KD performed the studies. AT, FW, HJ, SS and HT performed the biochemical analyses. ME did the statistical analysis with NW and LMY. GN prepared the chemicals for administration.