One explanation may relate to metabolic differences between species. Methamidophos can cause a cholinergic crisis in hens so strong that it will be lethal before the onset of clinical signs of OPIDN. Therefore, in hens, the enantiomer with a higher affinity for AChE may be less metabolized than in other species, and the enantiomer that exhibits greater affinity for NTE may be less

metabolized in humans. Buparlisib mouse Studies done only with tissue from hens could lead to the erroneous conclusion that methamidophos does not induce OPIDN in humans. Therefore, the combination of in vitro studies on human and hen enzymes and studies of metabolism in hens could predict whether the OP is capable of generating OPIDN in both species ( Battershill et al., 2004). There are several research studies that describe calpain activation in hens after intoxication by a neuropathic OP (El-Fawall et al., 1990, Choudhary and Gill, 2001 and Emerick et al., 2010). In Wallerian-type degeneration an excessive intake of calcium

by the cell can activate calpain. This enzyme promotes digestion of the terminal portion of axons, preventing the transmission of nerve impulses to the post-synaptic cells (Moser et al., 2007). In the present work, an in vitro calpain assay demonstrates that only mipafox was able to promote calpain activation. BAY 80-6946 This effect was greater with human neuroblastoma cells, probably because they are relatively pure compared to the multiple cell types found in a brain homogenate. An early study by Ehrich et al. (1997) showed that capability to cause or not cause OPIDN could be predicted by ratios of the IC50 values in human and mouse PAK5 neuroblastoma cells. Later, Sogorb et al.

(2010) proposed an alternative methodology to predict whether an OP is able to induce OPIDN. This method is based on the comparison of the in vitro inhibition (and aging of NTE) of both enzymes (NTE and AChE) in human and hen cells. The authors tested 10 OPs (6 neuropathic and 4 non-neuropathic), and stated that if the IC50NTE/IC50AChE ratio is greater than five, then the compounds would not be able to induce the neuropathy. This was because the concentrations necessary for inhibition and aging of greater than 70% of NTE would not be compatible with the survival of individuals due to strong cholinergic crisis before the onset of delayed effects. However, if the IC50NTE/IC50AChE ratio is less than five, the OP may be a neuropathic compound if it has the ability to induce the “aging” reaction. Applying this hypothesis to the results of this in vitro study, we conclude that the (−)-methamidophos form would not be able to generate OPIDN in humans and hens, even if the aging reaction of NTE was to occur. However, other variables exist in vivo, such as differences in metabolism.