Neuropathy delayed

Phosphonothioate Esters of Phenols. Phosphonates with a single P—C bond are highly toxic and persistent iasecticides but have not been used extensively because some compounds produce delayed neuropathy leading to irreversible paralysis ia higher animals, including humans. Such compounds specifically inhibit an enzyme, neurotoxic esterase, that is responsible for the growth and maintenance of long nerve axons (31,32). 

This process of aging is believed to be critical in the development of delayed neuropathy, after NTE has been phosphorylated by an OP (see Chapter 10, Section 10.2.4). It is believed that most, if not all, of the B-esterases are sensitive to inhibition by OPs because they, too, have reactive serine at their active sites. It is important to emphasize that the interaction shown in Fignre 2.11 occurs with OPs that contain an oxon group. Phosphorothionates, which contain instead a thion group, do not readily interact in this way. Many OP insecticides are phosphorothionates, but these need to be converted to phosphate (oxon) forms by oxidative desulfuration before inhibition of acetylcholinesterase can proceed to any significant extent (see Section 2.3.2.2). 

A few OP compounds cause delayed neuropathy in vertebrates because they inhibit another esterase located in the nervous system, which has been termed neuropathy target esterase (NTE). This enzyme is described in Chapter 10, Section 10.2.4. OPs that cause delayed neuropathy include diisopropyl phosphofluoridate (DFP), mipafox, leptophos, methamidophos, and triorthocresol phosphate. The delay in the appearance of neurotoxic symptoms following exposure is associated with the aging process. In most cases, nerve degeneration is not seen with initial inhibition of the esterase but appears some 2-3 weeks after commencement of exposure, as the inhibited enzyme undergoes aging (see Section 16.4.1). The condition is described as OP-induced delayed neuropathy (OPIDN). 

Neuropathy target esterase (NTE) An esterase of the nervous system whose inhibition by certain OPs (e.g., mipafox, leptophos) can lead to the development of delayed neuropathy. 

Johnson, M.K. (1992). Molecular events in delayed neuropathy Experimental aspects of neuropathy target esterase. In B. Ballantyne and T.C. Marrs, (1992). Clinical and Experimental Toxicology of Organophosphates and Carbamates 90-113. 

Chicken (White Vantress) 36-163 d 4.4 F 23 F (severe delayed neuropathy in 2/7 hens) Siegel et al. 1965 TAP1... 

Acute oral exposure to several organophosphate ester hydraulic fluids produced deaths in rabbits, chickens, and cows. The deaths were associated with severe cholinergic symptoms or symptoms of organophosphorus induced delayed neuropathy (OPIDN). (See Section 22.2 A for further details on the neurological effects.)... 

Many of the studies on the neurological effects of oral exposure to organophosphate ester hydraulic fluids in animals have employed chickens as models instead of the more commonly used rodent models. For reasons that are not well understood, organophosphate-induced delayed neuropathy can be induced in chickens and cats, but not in mice or rats (Abou-Donia and Lapadula 1990). 

No deaths occurred in rats after dermal exposure to Durad 220B, Durad 300, or Durad 110 under occluded conditions for 24 hours at dosage levels of 2,000 mg/kg (FMC 1990a). Dermal exposure to 2,890 mg/kg doses of a cyclotriphosphazene hydraulic fluid for 24 hours under occluded conditions likewise produced no deaths in rabbits (Kinkead et al. 1992c MacEwen and Vernot 1985). Deaths associated with severe cholinergic symptoms and symptoms of delayed neuropathy occurred in a group of 50 cattle treated dermally with about 1.52 L of waste from reclamation of a Fyrquel hydraulic fluid (Julian et al. 1976). 

A recent series of experiments with cats, chickens, or rats exposed to [uniformly labeled 14C-phenyl]-TOCP shows that a complex array of oxidized and dearylated metabolites are found in excreta and various tissues including the liver, kidney, testis, and brain (Abou-Donia et al. 1990a, 1990b Nomeir and Abou-Donia 1986 Somkuti and Abou-Donia 1990). Cats and chickens, like humans, are sensitive to TOCP-induced delayed neuropathy (Baron 1981). A similar array of oxidized and dearylated derivatives of tri-para-cresyl phosphate (but no cyclic metabolites) were identified by mass spectrometry in the urine and... 

Reliable NOAELs and LOAELs for intermediate oral exposure are restricted to a 90-day NOAEL of 50 mg/kg/day for systemic toxicity in rats (a species that is not sensitive to the neuropathic effects of organophosphate esters) exposed to Pydraul 90E for 90 days and NOAELs and LOAELs for delayed neuropathy in chickens exposed to Durad 110. In chickens exposed to Durad 110 for 28 days, a NOAEL of444 mg/kg/day and LOAEL of 1,333 mg/kg/day were identified (FMC 1986) when the duration was increased to 90 days, the NOAEL was 20 mg/kg/day and the LOAEL was 90 mg/kg/day (FMC 1986). These data are inadequate for derivation of an intermediate oral MRL for organophosphate ester hydraulic fluids. As discussed under the acute-duration oral MRL section, there is uncertainty regarding extrapolation of chicken doses to human doses. 

A third enzyme may have limited potential as a measure of exposure. Neurotoxic esterase, also known as neuropathy target esterase (NTE), is inhibited by certain organophosphate esters. When brain NTE is inhibited above 70% for acute or possibly as low as 50% for repeated exposures, there is a consensus that delayed neuropathy is likely. NTE also is found in lymphocytes and platelets (Lotti et al. 1984). The... 

Organophosphate Ester Hydraulic Fluid. The most widely examined target of organophosphate ester hydraulic fluids is the nervous system. Two types of neurological effects have been observed following exposure to certain organophosphate ester hydraulic fluids cholinergic symptoms associated with acetylcholinesterase inhibition and delayed neuropathy (OPIDN). 

A potentiation of neuropathy has been observed in studies involving administration of -hexane or methyl -butyl ketone with O-ethyl-O-4-nitrophenyl phenylphosphonothioate (EPN) (Abou-Donia 1983 Abou-Doniaetal. 1985). Administration of each compound individually resulted in peripheral neuropathy. The peripheral neuropathy observed when /7-hexane or methyl n-butyl ketone was administered simultaneously with EPN was more severe and had an earlier onset (Abou-Donia et al. 1985). The potential interactive effect of multiple exposures to different organophosphorus pesticides on delayed neuropathy has not been characterized (Chemiack 1988). 

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