The results supported previous in vitro ( Bertolazzi et al., 1991 and Emerick et al., 2012a)

screening that suggested (+)-methamidophos as the more likely than (−)-methamidophos learn more to induce OPIDN in humans and hens. In the present study hens were given pure enantiomers and racemic with proper protection (atropine) from cholinergic crisis. Because methamidophos can cause OPIDN in people (McConnell et al., 1999 and Senanayake and Johnson, 1982), early inhibition of NTE activity of at least 70% is generally used to identify OPIDN potential. In this study, such inhibition was noted with 500 mg/kg TOCP. Although NTE inhibition with (+)-methamidophos was less than that, it could be expected that a higher dose would reach 70%. Even 50 mg/kg (+)-methamidophos could cause

behavioral deficits and some lesions in the spinal cord, evidence that OPIDN may occur even when NTE is not 70% inhibited (Ehrich et al., 1995). OPIDN follows NTE inhibition and aging of OP-inhibited enzyme, but aging was not measured in this study. Others have suggested that aging is slower and/or less intense for methamidophos than for TOCP (Vilanova et al., 1987, Johnson et al., 1989, Sogorb et al., 1997 and Kellner et al., 2000). In addition to being measured shortly after dosing, NTE activity was also measured at time of sacrifice, 21 days after OP dosing. At that time NTE inhibition was no longer inhibited, suggesting that the enzyme had been resynthesized (Glynn, 2006). All enantiomers Pirfenidone mw of methamidophos dosed tuclazepam at 50 mg/kg

could cause 80% inhibition of AChE when measured 24 h after dosing. This contrasts with the 20% inhibition of AChE seen after TOCP. These results suggest that the great AChE inhibition that followed (±)- and (−)-methamidophos would not allow inhibition and aging of more than 70% of NTE and survival of the hens for 21 days. Sogorb et al. (2010) suggested that if the IC50NTE/IC50AChE ratio is greater than five, then the compounds would not be able to induce the neuropathy because the concentrations necessary for NTE inhibition and aging would not be compatible with the ability of individuals to survive with a strong acute cholinergic crisis. An IC50NTE/IC50AChE ratio less than five would suggest that the OP may be a neuropathic compound if it has the ability to induce the “aging” reaction. Calculating % of NTE inhibition/% of AChE inhibition ratio for each compound tested in the present study provides ratios of 4.4 and 0.7 for TOCP and (+)-methamidophos, respectively. For (±)- and (−)-methamidophos the ratios are both 0.2. Our results allow us to say that the enantiomer responsible for delayed effects is the (+)-methamidophos and the three isoforms of methamidophos generate similar acute effects in hens. In the present experiments calpain activity was measured because OPIDN develops a Wallerian-type axonal degeneration and this protease has been implicated in this process (El-Fawal et al.