Delayed neurotoxic effect

No NOAELs or LOAELs were identified for toxic effects in humans after inhalation exposure to organophosphate ester hydraulic fluids. Reliable NOAELs and LOAELs for acute inhalation exposure are restricted to 4-hour NOAELs for systemic effects in rats exposed to Fyrquel 220 or Durad MP280 and 4-hour LOAELs for mild lethargy in rats exposed to Durad MP280 and Fyrquel 220 (Gaworski et al. 1986). The study identifying these NOAEL and LOAEL values did not measure cholinesterase inhibition, did not allow sufficient follow-up time for the development of delayed neurotoxic effects, and used a... 

Johnson MK, Barnes JM. 1970. Age and the sensitivity of chicks to the delayed neurotoxic effects on some organophosphorus compounds. Biochem Pharmacol 19 3045-3047. 

Some OP compounds induce delayed neurotoxic effects ("delayed neuropathy") after acute poisoning. This delayed neurotoxic action is independent of cholinesterase inhibition but related to phosphorylation of a specific esterasic enzyme in the nervous tissue, called "neurotoxic esterase" or "neuropathy target esterase" (NTE) (Johnson, 1982). NTE is present in the nervous tissue, liver lymphocytes, platelets, and other tissues, but its physiological function is unknown. There is a rather large inter-individual variation of lymphocyte and platelet NTE activity (Table 2). 

A number of OPC are capable of rendering a delayed neurotoxic effect (DNE). This effect becomes apparent gradually, after a certain latent period (usually 14 to 21 days, sometimes 1 to 5 years after the acute poisoning survived) and is characterized clinically by the development of ataxia, muscular weakness, paresis and paralysis of the extremities. Morphologically, it is characterized by fiber demyelinization of spinal pathways and peripheral nerves. Till present time, near 40,000 cases have been described, when paresis and paralysis developed in human beings as a result of their exposure to OPC (TOCP, mipaphox, chloropyrophos, trichlorfon, etc.) [1],... 

This patient had taken ecstasy 10 times during the year before, the last time about 3 months before the onset of symptoms. Apart from marijuana, he denied using other substances. He was treated with maximal tolerable doses of levodopa and pramipexole, without improvement. The authors reported that they had no explanation for this patient s symptoms, other than the use of ecstasy. They felt that the parkinsonian symptoms most closely resembled MPTP-induced parkinsonism. They further postulated that this could be a delayed neurotoxic effect of ecstasy in the substantia nigra and striatum and could have occurred as a result of neuronal damage by free radicals. 

Husain, K.R., R. Vijayaraghavan, S.C. Pant, S.K. Raza, and K.S. Pandey. 1993. Delayed neurotoxic effect of sarin in mice after repeated inhalation exposure. J. Appl. Toxicol. 13 143-145. 

No clinical or experimental evidence is available to indicate that VX causes delayed neuropathy in humans (Munro et al., 1994). Chickens injected subcutaneously with supralethal doses of VX (10, 100, or 150 /rg/kg, following treatment with antidotes to protect against acute toxicity) exhibited no signs of a delayed neurotoxic response (Goldman et al., 1988). However, QL, a chemical intermediate of VX, has been reported to cause delayed neurotoxic effects in hens dosed at 635 mg/kg (Olajos et al., 1986). The available data indicate that delayed neuropathy in humans exposed to VX is unlikely. 

Johnson, M.K. (1969). The delayed neurotoxic effect of some organophosphorus compounds. Identification of the phosphorylation site as an esterase. Biochem. J. 114 711-17. 

Johnson, M.K. (1974). The primary biochemical lesion leading to the delayed neurotoxic effects of some organophosphoms esters. J. Neurochem. 23 785-9. 

Many experimental species are vulnerable to the delayed neurotoxic effects of OF compounds, such as TOCF, although It Is accepted chat neurocoxlc doses vary markedly from one species to another. Rodents are relatively resistant and fowl very susceptible hens are widely used to assay AChE compounds for... 

Notes Human SH-SY5Y neuroblastoma cells were Incubated for 1 h with different concentrations of each organophosphate (OP). Cytotoxicity was measured by the neutral red assay. Results represent the IC50 values for inhibition of AChE and NTE activities and for cytotoxicity. DBVP = 0,0-dibutyl 0-(2,2-dlchlorovlnyl) phosphate DOVP = 0,0-dloctyl 0-(2,2-dlchlorovlnyl) phosphate. A high ratio of NTE IC50/AChE IC50 Indicates that the OP is likely to cause acute rather than delayed neurotoxic effects in vivo. 

No specific therapy is known as a treatment for victims presenting signs of Ginger Jake paralysis as this is a delayed neurotoxic effect. It would be prudent to determine the cause of exposure to ensure that the victim is no longer exposed to TOCP and provide supportive care. The victim should be transported to a hospital for evaluation. 

These pesticides inhibit acetylcholine esterase and produce effects similar to, but much milder than, nerve agents. Some of these pesticides exhibit significant delayed neurotoxic effects. Some are readily stored in body fat, which may increase the period between exposure and manifestation of symptoms as well as prolong the time required for the body to excrete the toxins. 

Johnson, M.K., Organophosphorus esters causing delayed neurotoxic effects. Mechanism of action and structure / activity studies, Arch. Toxicol. 34,259-288,1975. 

OP compounds that produce delayed neurotoxic effects are esters of phosphtsrus-containing acid.s. More than 35 years ago, tri-o-cresyl phosphate (TOCP) was known to produce delayed neurotoxic effects in humans and chickens characterized by ataxia and weakness of the limbs, developing 10-14 day.s after exposure (John,son. 1969). This syndrome is called OP-induced delayed neuropathy (OPIDN). TOCP and certain other compounds have minimal or no anti-AChE... 

Johnson, M. K. (1975). Organophosphorus csiers causing delayed neurotoxic effects Mechanism of action and structure-activity studies. Toxicol. 34, 2.59-288. 

The delayed neurotoxic effect, also called OrganoPhosphate Induced Delayed Neurotoxicity (Neuropathy) (OPIDN), is characterized by sensoric and motoric disturbances of the peripheral nervous system (degeneration of... 

The delayed neurotoxic effect can be monitored by the determination of neurotoxic esterase. The determination of this enzyme in the lymphocytes soon after injection of neurotoxicants (15-30 min) permits an assessment of the progress of delayed neurotoxicity (K22). In vitro techniques for the assessment of neurotoxicity have been elaborated by Harry et al. (H3). 

Tkachenko II, Kagan YS, Kokshareva NV, Badaeva LN (1985) Delayed neurotoxic effects of a new fungicide-aphos. Farmakologiya i Toksikologiya 6 80-83. 

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