Organophosphorus compounds, toxic effects

The toxicity of the P-halidc anhydrides, like that of phosphoroxychloride (POCl3) and of other organophosphorus compounds discussed earlier in this section, is due to their high efficiency as irreversible inactivators of acetylcholinesterase [157]. The main target organs for the lethal effects of these chemical weapons are the brain and diaphragm. As for the detoxification of the P-halide anhydrides, it can occur by a number of biochemical mechanisms, namely chemical hydrolysis, enzymatic hydrolysis, and binding to hydrolases such as carboxylesterases, cholinesterases, and albumin [68][158][159]. 

Irreversible inhibition in an organism usually results in a toxic effect. Examples of this type of inhibitor are the organophosphorus compounds that interfere with acetylcholinesterase (see Box 7.26). The organophosphorus derivative reacts with the enzyme in the normal way, but the phosphory-lated intermediate produced is resistant to normal hydrolysis and is not released from the enzyme. 

Two factors contribute to the safety of oximes in the treatment of acute poisoning by organophosphorus compounds recommended doses are small, compared with doses likely to cause even mild toxic effects in normal subjects and adverse effects of oximes are reduced in the presence of poisoning by an organophosphorus compound. 

Two examples of toxicity, where the target is known, are carbon monoxide, which interacts specifically with hemoglobin, and cyanide, which interacts specifically with the enzyme cytochrome a3 of the electron transport chain (see chap. 7). The toxic effects of these two compounds are a direct result of these interactions and, it is assumed, depend on the number of molecules of the toxic compound bound to the receptors. However, the final toxic effects involve cellular damage and death and also depend on other factors. Other examples where specific receptors are known to be involved in the mediation of toxic effects are microsomal enzyme inducers, organophosphorus compounds, and peroxisomal proliferators (see chaps. 5-7). 

Although a particular organophosphorus compound may be rapidly metabolized and therefore not accumulate in the animal, chronic dosing may cause a cumulative toxic effect because of the slow rate of reversal of the inhibition. Thus, the rate of regeneration may be slow... 

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... 

For example, no difference in the toxicity of organophosphorus compounds to larvae of the midge Chrironomus riparius was observed between pulsed and continuous exposures (Kallander et al. 1997). In the same study, however, two 1-hour pulses caused significantly fewer symptoms of intoxication than 2 hours of continuous exposure to carbamate compounds, when animals were placed in clean water for at least 2 to 6 hours between treatments (Kallander et al. 1997), suggesting that detoxification or elimination of the toxicant during the toxicant-free period can reduce the toxic effects of the earlier exposures. 

ORGANOPHOSPHORUS PESTICIDES There are no simple direct chemical tests for organophosphorus compounds. The toxic effects e usually associated with depression of the cholinesterase activity of the body, and measurement of the plasma or serum cholinesterase can be used, therefore, as an indication of organophosphorus poisoning. 

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