Neuropathy, delayed organophosphorus compounds

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). 

About 1-A days after apparent recovery from the acute poisoning, an intermediate syndrome of muscle paralysis can occur, requiring prolonged ventilation before strength returns. A minority of organophosphorus compounds can cause a delayed, chronic, peripheral neuropathy (organophosphorus-induced delayed neuropathy - OPIDN), first manifest some weeks after acute poisoning. 

Poisoning by organophosphorus compounds can be treated, and although the acute symptoms can be alleviated, the delayed neuropathy cannot. There are two treatments that may be used, both involving antidotes ... 

This group of compounds is used as pesticides and nerve gases. The structure and therefore metabolism and potency varies. However, they all act in a similar manner. There are two toxic effects, cholinesterase inhibition and delayed neuropathy, but all OPs do not necessarily cause both. The cholinesterase inhibition results from the similarity between the organophosphorus compound and acetylcholine. The organophosphorus compound therefore acts as a pseudosubstrate but blocks the enzyme, in some cases, permanently. This is because the... 

N. Aldridge, Postscript to the symposium on organophosphorus compound-induced delayed neuropathy. Chem. Biol. Interact. 87(l-3) 463, 1993. 

FIGURE 57.5. Subclasses of neuropathy target esterase (NTE) inhibitors. Type A inhibitors include phosphates, phosphonates, and phosphoramidates these are neuropathic and capable of aging. T pe B inhibitors include phosphinates, sulfonates, and carbamates these are nonneuropathic and not capable of aging. However, inhibition of NTE with a type B inhibitor will protect against organophosphorus compound-induced delayed neurotoxicity (OPIDN) from subsequently administered type A inhibitors. Reproduced with permission from Richardson (2005). 

Ehrich M, Correll L, Veronesi B. Acetylcholinesterase and neuropathy target esterase inhibitions in neuroblastoma cells to distinguish organophosphorus compounds causing acute and delayed neurotoxicity. Fund Appl Toxicol. 1997 38 55-63. 

The term delayed neurotoxicity may be used to describe any type of toxicity to the nervous system involving a delay between the precipitating chemical exposure and the appearance of neurological signs or symptoms. However, this designation usually refers to organophosphorus (OP) compound-induced delayed neurotoxicity (or delayed neuropathy) (OPIDN), also known as OP compound-induced delayed polyneuropathy (OPIDP). 

Aldridge WN, Barnes JM and Johnson MK (1969). Studies on delayed neuropathy produced by some organophosphorus compounds. Ann NY Acad Sci, 160, 314-322. 

Certain organophosphates may also induce delayed polyneuropathy, usually 2-3 weeks after a single exposure. The symptoms are tingling of hands and feet, sensory loss, progressive muscle weakness, and ataxia. Also, certain organophosphorus compounds are poor inhibitors of AChE but may, however, bind to another esterase, known as neuropathy target esterase (NTE) and induce delayed neuropathy. 

It is known that human exposure to organophosphorus compounds can result in a variety of acute toxic effects. These arise primarily as a result of the inhibition of acetylcholinesterase. Signs of acute toxicity are due to effects on the central nervous system (anxiety, ataxia, hypotension), to muscarinic effects (wheezing, cough, rhinitis) and to nicotinic effects (muscle weakness, mydriasis and tachycardia). Other acute effects include chest tightness, abdominal cramps, confusion and convulsions. With some organophosphorus compounds, a specific syndrome may develop. This is delayed peripheral neuropathy or OP-induced delayed neuropathy (OPIDN). (For a more detailed discussion on the toxicity of organophosphorus compounds see Chapter 10.)... 

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