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Indoor Air Pollution
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain OP esters. It is characterized by distal degeneration of some axons of both the peripheral and central nervous systems (CNSs) occurring 1–4 weeks after single or short-term exposures. Cramping muscle pain in the lower limbs, distal numbness, and paresthesia occur, followed by progressive weakness, depression of deep tendon reflexes in the lower limbs and, in severe cases, in the upper limbs. Signs include high-stepping gait associated with bilateral foot drop and, in severe cases, quadriplegia with foot and wrist drop as well as pyramidal signs. In time, there might be significant recovery of the peripheral nerve function but, depending on the degree of pyramidal involvement, spastic ataxia may be a permanent outcome of severe OPIDP. Human and experimental data indicate that recovery is usually complete in the young. At onset, the electrophysiological changes include reduced amplitude of the compound muscle potential, increased distal latencies and normal or slightly reduced nerve conduction velocities. The progression of the disease, usually over a few days, may lead to nonexcitability of the nerve with electromyographical signs of denervation. Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination. Neuropathy target esterase (NTE) is thought to be the target of OPIDP initiation. The ratio of inhibitory powers for acetylcholinesterase and NTE represents the crucial guideline for the etiological attribution of OP-induced peripheral neuropathy. In fact, premarketing toxicity testing in animals selects OP insecticides with cholinergic toxicity potential much higher than that to result in OPIDP. Therefore, OPIDP may develop only after very large exposures to insecticides, causing severe cholinergic toxicity. However, this was not the case with certain triaryl phosphates (TAPs) that were not used as insecticides but as hydraulic fluids, lubricants, and plasticizers and do not result in cholinergic toxicity. Several thousand cases of OPIDP as a result of exposure to tri-ortho-cresyl phosphate have been reported, whereas the number of cases of OPIDP as a result of OP insecticide poisoning is much lower. In this article “Organophosphate-induced delayed polyneuropathy”, they mainly discuss OP pesticide poisoning, particularly when caused by CPF, dichlorvos, isofenphos, methamidophos, mipafox, trichlorfon, trichlornat, phosphamidon/mevinphos, and by certain carbamates. They also discuss case reports where neuropathies were not convincingly attributed to fenthion, malathion, omethoate/dimethoate, parathion, and merphos. Finally, several observational studies on long-term, low-level exposures to OPs that sometimes reported mild, inconsistent, and unexplained changes of unclear significance in peripheral nerves are briefly discussed.
Impaired neuromuscular function by conjoint actions of organophosphorus insecticide metabolites omethoate and cyclohexanol with implications for treatment of respiratory failure
Published in Clinical Toxicology, 2021
Kosala N. Dissanayake, Robert Chang-Chih Chou, Adrian Thompson, Filip Margetiny, Charlotte Davie, Scott McKinnon, Vishwendra Patel, Lester Sultatos, Joseph J. McArdle, Richard E. Clutton, Michael Eddleston, Richard R. Ribchester
Next, we measured the functional effects of i.v. administration of omethoate. We attached a force transducer to one pelvic limb of eleven anaesthetised pigs and used this transducer to obtain MMG recordings of contractions of pelvic limb muscles, in response to stimulation of the common peroneal nerve. We continuously monitored the MMG responses of muscles to train-of-four (TOF) stimulation (2 Hz, every 20–30 s). Tetanic responses were tested in nine of the animals by brief stimulation (50 Hz, 0.5–2 s duration) delivered at 15–30 min intervals. Omethoate was infused i.v. in 11 animals at doses of 2–4 mg kg−1 h−1 , following bolus i.v. injections of 20–40 mg kg−1. This resulted in plasma concentrations of omethoate ranging from 87.3 to 817 µM, overlapping the range we measured following dimethoate EC40 gavage in our previous study (50–249 µM) [27]. The anaesthetised animals all showed overt clinical signs of AChE poisoning as infusion of omethoate progressed, notably profuse spontaneous salivation.
Determination of enzymatic kinetics of metabolism of dimethoate and omethoate in rats and humans
Published in Xenobiotica, 2023
Gopinath Nallani, Appavu Chandrasekaran, Kelem Kassahun, Li Shen, Rick Reiss, Paul Whatling
The in vivo PK data showed that significant amounts of omethoate were formed in rats following administration of dimethoate supporting the in vitro findings. Also, the oral bioavailability was high, 73 – 80%. Excretion data from a previous study with 14C-dimethoate showed absorption of 85–91%, following oral administration to rats, supporting the high oral bioavailability estimated in this study. The in vivo pharmacokinetics study in adult rats was conducted in males only to minimise the number of animals used.