Organophosphates acute toxicity

Our group compared in Wistar rats the acutely toxic organophosphate (OP) paraoxon with fenthion, one of the agents frequently involved in human IMS. The clinical symptoms, the occurrence of muscle fiber necrosis and histochemical assessment of neuromuscular junction AChE activity in muscle biopsies, biochemical assessment of brain AChE activity, and EMG parameters including repetitive nerve stimulation at various frequencies were studied at various lime points. 

A sizable proportion of the stocks listed in the table below contain persistent organochlorines, such as DDT, dieldrin and lindane, which are banned in many countries (Table 10). Obsolete stocks also contain acutely toxic organophosphates such as fenitrothion and malathion, as well as many chemicals with no identification whatsoever. 

Enzyme Inhibition. Some materials produce toxic effects by inhibition of biologically vital enzyme systems, leading to an impairment of normal biochemical pathways. The toxic organophosphates, for example, inhibit the cholinesterase group of enzymes. An important factor in thek acute toxicity is the inhibition of acetylocholinesterase at neuromuscular junctions, resulting in an accumulation of the neurotransmitter material acetylcholine and causing muscle paralysis (29) (see Neuroregulators). 

Organophosphate insecticides also inhibit RBC-ACHE and PCHE. Inhibition of ACHE in erythrocytes is assumed to mirror inhibition of ACHE in the nervous system, which is the receptor of the toxic action, to some extent. Therefore, measurements of RBC-ACHE and PCHE are used for biological monitoring of exposure to OP insecticides (Maroni, 1986). Inhibitions of RBC-ACHE and PCHE activities are correlated with intensity and duration of exposure, although at different levels for each OP compound. Blood ACHE, being the same molecular target as that responsible for acute toxicity in the nervous system, is a true indicator of effect, while PCHE can only be used as an indicator of exposure. 

The acute toxic effects of the cholinesterase inhibitors, like those of the direct-acting agents, are direct extensions of their pharmacologic actions. The major source of such intoxications is pesticide use in agriculture and in the home. Approximately 100 organophosphate and 20 carbamate cholinesterase inhibitors are available in pesticides and veterinary vermifuges used in the USA. 

Exposure to some organophosphate cholinesterase inhibitors results in a delayed neuropathy characterized by degeneration of axons and myelin. This effect is not associated with the inhibition of acetylcholinesterase, but rather with the inhibition of an enzyme described as neuropathy target esterase (NTE) however, the exact mechanism of toxicity is not yet fully understood (Munro et al., 1994). For some organophosphate compounds, delayed neuropathy can be induced in experimental animals at relatively low exposure levels, whereas for others the effect is only seen following exposure to supralethal doses when the animal is protected from the acute toxic effects caused by cholinesterase inhibition. 

It has been possible to devise antidotes for organophosphate poisoning because the underlying mechanism by which they cause acute toxicity is understood. These are very effective for the rapid treatment of acute poisoning episodes but are ineffective for peripheral neuropathy or if poisoning occurred some days previously. 

Gupta, R.C., Dettbam, W-D. (1992). Potential of memantine, d-tubocurarine and atropine in preventing acute toxic myopathy induced by organophosphate nerve agents soman, sarin, tabun and VX. NeuroToxicology 13 500-14. 

Cholinesterase inhibition may persist for a period of days to weeks. Therefore, repeated exposure to azamethiphos over a period of time may result in the accumulation of enzyme inhibition and onset of acute toxicity. Azamethiphos does not appear to be capable of eliciting organophosphate-induced delayed neuropathy. Likewise, azamethiphos does not appear to be carcinogenic. 

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