Chlorpyrifos-induced delayed polyneuropathy

Abstract

Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60-90 mg/kg p.o., corresponding to 4-6 times the estimated LD50. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (greater than 70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5-6 days. High AChE inhibition (greater than 90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10-20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A-esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.

Relative Inhibitory Potencies of Chlorpyrifos Oxon, Chlorpyrifos Methyl Oxon, and Mipafox for Acetylcholinesterase Versus Neuropathy Target Esterase

“…Adjusting the k i obtained in the present work to account for the temperature difference between the two studies (Aldridge & Reiner, 1972) yields a value of 7.4 µM −1 min −1 for hen brain microsomal AChE, which is within the range obtained by Amitai et al (1998). Capodicasa et al (1991) investigated the time course of inhibition of hen brain AChE and NTE by CPO under conditions that gave nonlinear kinetics and determined 20-min I 50 values of 6 and 150 nM for AChE and NTE, respectively. Their RIP was therefore 25.…”

“…Using kinetic determinations of k i values obtained from linear kinetics, the corresponding RIP was found to be 107 (Richardson et al, 1993). In either case, it is clear that the RIP of CPO is >>1, indicating that CPS could not produce OPIDN at sublethal doses, consistent with experimental results in animals (Capodicasa et al, 1991;Richardson et al, 1993) and clinical data on humans (Lotti et al, 1986;Moretto & Lotti, 1998).…”

“…Nevertheless, as had been observed for CPO in previous studies using hen brain homogenates (Capodicasa et al, 1991;Richardson et al, 1993), it may be hypothesized that the RIP for its methyl homologue, CPMO, would also be >>1 and greater than the RIP for CPO. This contention arises from structure-activity studies showing that decreasing the carbon chain length of alkyl substituents attached to phosphorus tends to increase the RIP and decrease the neuropathic potential for a given homologous series of dialkyl phosphates (Makhaeva et al, 1998;Richardson, 1992).…”

“…Based on fixed-time I 50 values under conditions of nonlinear kinetics in hen brain homogenates (20 min at 37°C), the RIP for CPO has been determined to be 25 (Capodicasa et al, 1991). Using kinetic determinations of k i values obtained from linear kinetics, the corresponding RIP was found to be 107 (Richardson et al, 1993).…”

“…This contention arises from structure-activity studies showing that decreasing the carbon chain length of alkyl substituents attached to phosphorus tends to increase the RIP and decrease the neuropathic potential for a given homologous series of dialkyl phosphates (Makhaeva et al, 1998;Richardson, 1992). If the RIP data for CPMO and CPO were to support the prediction from structure-activity considerations, then this would indicate that the potential for CPMS to produce OPIDN would be even lower than that of CPS, which is already known to be incapable of producing OPIDN at sublethal doses (Capodicasa et al, 1991;Moretto & Lotti, 1998;Richardson, 1995;Richardson et al, 1993).…”