Mipafox toxicity

The rapid growth in the use of OPs and the proliferation of new active ingredients and formulations was not without its problems. Some OPs proved to be too hazardous to operators because of very high acute toxicity. A few were found to cause delayed neurotoxicity, a condition not caused by ChE inhibition (e.g., mipafox, lepto-phos). There was also the problem of the development of resistance, for example, by... 

Toxicity of organophosphates can be potentiated 15-20-fold in rats and mice by pretreatment with a metabolite of tri-O-cresylphosphate, CBDP (2-0-cresyl)-4H-l,3,2-benzodioxa-phosphorin-2-oxide), which is an irreversible inhibitor of CarbEs. In similar studies, tetraisopropylpyrophosphoramide (iso-OMPA), or mipafox, an organophosphate-irreversible inhibitor of CarbEs, potentiates three-to fivefold the toxicity of several OPs (soman, DFP, and methylparathion) and carbamates (carbofuran, aldicarb, propoxur, and carbaryl). Inhibition of CarbEs by CBDP, iso-OMPA, or mipafox pretreatment, particularly in plasma, liver, heart, brain, and skeletal muscles, is a major contributory factor in the potentiation of toxicity of organophosphates and carbamates. Thus, the toxicity of any drug, pesticide, or other type of agent that is normally detoxified by CarbEs, could be potentiated by pre-exposure to an organophosphorus or other carboxylesterase inhibitor. 

Fluorophosphates are also highly toxic and relatively volatile. Sarin and soman are chemical warfare agents. Diisopropyl fluorophosphate (DFP) is often used by biochemists to study serine-active enzymes. Mipafox and DFP cause OPIDN in humans and experimental animals. 

AChE inhibition induced by 0.03-3 p.,Af paraoxon, or 3-60 p.jW and mipafox is reduced by pretreatment of the toxicant with organophtisphorus hydrolase. 

The toxicity of dimethoate to mice may be increased by pre-treatment with phenobarbitone [58] or pentobarbitone [59], whereas the toxicities of phos-phamidon, dicrotophos and their Ai-dealkylated derivatives are decreased [58]. Dimethoate requires oxidative activation, yet the vinyl phosphates do not. In vitro studies confirm the induction of mouse hepatic microsomal enzymes by phenobarbitone pre-treatment, which activate schradan, mala-thion and parathion [60]. Microsomal induction by pre-treatment with pentobarbitone stimulates not only the activation of certain organophos-phates, but also their catabolism, thereby reducing their toxicity, for example mipafox [59]. 

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