https://www.amjmed.com/article/0002-9343(71)90337-8/pdf

Poisoning due to organophosphate insecticides. acute and chronic manifestations

Neuropharmacological Mechanisms of Nerve Agent-induced Seizure and Neuropathology

In certain animals, including humans, exposure to some organophosphorus esters causes delayed neurotoxicity (OPIDN). The clinical condition becomes manifest after a delay period, first as ataxia, followed by paralysis. Lesions are characterized by degeneration of axons with subsequent secondary degeneration of myelin in the peripheral and central nervous systems. Recovery is only likely in mild cases, whereas more severe cases show symptoms of an upper motor neuron lesion in the lower limbs. The risk of use of these chemicals is related not only to human sensitivity to this syndrome, but also to the fact that in most disasters involving OPIDN, humans were the prime victims. Therefore, the neurotoxic action of a chemical is of great significance, since pesticides with this property are not recommended for use. Although OPIDN has been recognized for over a half a century, its mechanism of action is still unknown. It is believed, however, that the initial target in OPIDN is the phosphorylation of a neurotoxicity target protein in the nervous system. Study of the relationship between the chemical structure of organophosphorus esters and their neurotoxic potencies suggests that two hydrophobic areas may be present in the vicinity of the active site of the neurotoxicity protein. This article attempts to present an up-to-date overview of OPIDN. Despite the difficulties attributed to experimental variations of the reported studies, I feel that several significant points have come forth from the data.

Organophosphorus ester-induced delayed neurotoxicity.

Organophosphorus compounds are potent neurotoxic chemicals that are widely used in medicine, industry, and agriculture. The neurotoxicity of these chemicals has been documented in accidental human poisoning, epidemiological studies, and animal models. Organophosphorus compounds have 3 distinct neurotoxic actions. The primary action is the irreversible inhibition of acetylcholinesterase, resulting in the accumulation of acetylcholine and subsequent overstimulation of the nicotinic and muscarinic acetylcholine receptors, resulting in cholinergic effects. Another action of some of these compounds, arising from single or repeated exposure, is a delayed onset of ataxia, accompanied by a Wallerian-type degeneration of the axon and myelin in the most distal portion of the longest tracts in both the central and peripheral nervous systems, and is known as organophosphorus ester-induced delayed neurotoxicity (OPIDN). In addition, since the introduction and extensive use of synthetic organophosphorus compounds in agriculture and industry half a century ago, many studies have reported long-term, persistent, chronic neurotoxicity symptoms in individuals as a result of acute exposure to high doses that cause acute cholinergic toxicity, or from long-term, low-level, subclinical doses of these chemicals. The author attempts to define the neuronal disorder that results from organophosphorus ester-induced chronic neurotoxicity (OPICN), which leads to long-term neurological and neurobehavioral deficits. Although the mechanisms of this neurodegenerative disorder have yet to be established, the sparse available data suggest that large toxic doses of organophosphorus compounds cause acute necrotic neuronal cell death in the brain, whereas sublethal or subclinical doses produce apoptotic neuronal cell death and involve oxidative stress.

Organophosphorus Ester-Induced Chronic Neurotoxicity

The protection of animals against organophosphate poisoning by pretreatment with a carbamate.

The use of carbamates and atropine in the protection of animals against poisoning by 1,2,2-trimethylpropyl methylphosphonofluoridate

Tri-p-ethylphenyl phosphate is unique amongst the organophosphorus compounds which produce neurotoxic effects in not being an inhibitor of cholinesterase The dysfunction it produces is also marked by some unusual features Thus it produces a characteristic high-stepping gait which develops at varying periods after intramuscular injection but more regularly following oral administration A careful comparison of the character, onset and development of the effects of diisopropyl phosphorofluoridate (dyflos), tri-o-cresyl phosphate and tri-p-ethylphenyl phosphate has illustrated the differences between the two former substances and tri-p-ethylphenyl phosphate It has also confirmed a previous suggestion that this substance acts in a different manner from the other two, a suggestion supported by the histological evidence

Comparison of the functional effects of dyflos, tri-o-cresyl phosphate and tri-p-ethylphenyl phosphate in chickens.

Thirty-six alkyl organophosphorus compounds have been tested for neurotoxicity in the chicken The individual compounds were chosen to enable the importance of each portion of the molecule to be assessed in relation to the property of neurotoxicity Seventeen substances were found to be neurotoxic, fifteen for the first time All of these contained fluorine On the basis of the results reported, certain predictions have been made about the chemical structure of compounds which would be expected to be neurotoxic The importance of fluorine suggests that it plays a direct role in the development of the biochemical lesion, and this may occur as the result of its being carried by the molecule as a whole to specific areas in the nervous system By the action of cholinesterase, the P-F bond may be ruptured and ionic fluorine liberated where it blocks some metabolic cycle

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1960.tb01243.x

The relationship between the chemical structure and neurotoxicity of alkyl organophosphorus compounds.

Effect of oximes and atropine upon the development of delayed neurotoxic signs in chickens following poisoning by DFP and sarin.

The soluble methanesulphonate of the oxime 2-hydroxyiminomethyl-N-methylpyridinium (P2S) has been used to treat animals poisoned with sarin or ethyl pyrophosphate. The effect of the size of the dose, and its time of administration in relation to poisoning, have been examined. This oxime is very efficient in conjunction with atropine when given either before or after poisoning. About 30 mg./kg. seems to be the optimum therapeutic dose of the methanesulphonate. The significance of this optimum is discussed in relation to the treatment of accidental poisoning by organophosphate insecticides in man.

/pdf/2-hydroxyiminomethyl-n-methylpyridinium-methanesulphonate-5acrhbi5t5.pdf

D.R. Davies

Papers

The use of carbamates and atropine in the protection of animals against poisoning by 1,2,2-trimethylpropyl methylphosphonofluoridate

Comparison of the functional effects of dyflos, tri-o-cresyl phosphate and tri-p-ethylphenyl phosphate in chickens.

The relationship between the chemical structure and neurotoxicity of alkyl organophosphorus compounds.

Effect of oximes and atropine upon the development of delayed neurotoxic signs in chickens following poisoning by DFP and sarin.

2-Hydroxyiminomethyl-N-methylpyridinium methanesulphonate and atropine in the treatment of severe organophosphate poisoning.