Leptophos, neurotoxicity

A few OP compounds cause delayed neuropathy in vertebrates because they inhibit another esterase located in the nervous system, which has been termed neuropathy target esterase (NTE). This enzyme is described in Chapter 10, Section 10.2.4. OPs that cause delayed neuropathy include diisopropyl phosphofluoridate (DFP), mipafox, leptophos, methamidophos, and triorthocresol phosphate. The delay in the appearance of neurotoxic symptoms following exposure is associated with the aging process. In most cases, nerve degeneration is not seen with initial inhibition of the esterase but appears some 2-3 weeks after commencement of exposure, as the inhibited enzyme undergoes aging (see Section 16.4.1). The condition is described as OP-induced delayed neuropathy (OPIDN). 

Neurotoxic chemicals and motor neuropathy Chlorpyrifos, dichlorvos (DDVP), EPN, n-hexane, 2-hexanone, lead, lead chromate, lead II thiocyanate, leptophos, methamidophos, mipafox, omethoate, parathion, trichlor-fon, trichloronate, triorthocresyl phosphate Neurotoxic chemicals and sensorimotor neuropathy acrylamide, allyl chloride, arsenic and compounds, arsenic trichloride, calcium arsenate, carbon disulfide, dichloroacetylene, ethylene oxide, gallium arsenide, lead arsenate, mercuric chloride, mercuric nitrate, mercurous nitrate, mercury, nitrous oxide, phenyl arsine oxide, thallium and soluble compounds, thallous nitrate... 

Delayed neurotoxicity results from degeneration of the axons followed by demyelination (14,15,23). Clinical manifestation includes sensory disturbances, ataxia, weakness, muscle twitching and, in severe cases, complete flaccid paralysis ( 15). A fair number of organophosphate compounds are capable of inducing delayed neurotoxicity. Of the 250 organophosphates (not all pesticides) tested for delayed neurotoxicity in chickens, 47% (117 chemicals) showed positive responses (23). Notable examples of pesticides which possess this neurotoxicity are leptophos, EPN, merphos, dichlorvos, and... 

The development of efficient means for prevention of neurotoxic action of OPC (TOCP, mipaphox, dichlorvos, DFP, leptophos, aphos, etc.) of the delayed type (DNE) remains to be relevant. 

It appears that phenobarbital facilitates accelerated detoxication of either TOKP and leptophos or their intermediate products, and reduces accumulation of OPC in target tissues. Since the neurotoxic effect develops usually 2-3 weeks following a contact with OPC, reactivation of phosphorylated proteins in the nervous system and amplification of processes of their neutralization at the expense of enzyme induction can be used efficiently in this period. 

Note that the phosphorus atoms in leptophos and EPN are connected to four different groups and are therefore a mixture of two different stereoisomers, which may have different biological effects. With EPN only, the L(-) isomer is neurotoxic, whereas the L(+) is not. In fact when treated first with the L(+)isomer and thereafter with the L(-) isomer, the symptoms are less severe. Note also that an impurity, desbromo leptophos, in the technical product is 10 times more potent than leptophos as a neurotoxic agent. 

With respect to neurotoxins, there are a number of industrial chemicals (acrylamide, n-hexane, methyl n-butyl ketone, cresyl phosphate), pharmaceuticals (nitrofuradantoin, isoniazid), and pesticides (leptophos, Kepone ) which have been associated with neuropathic effects in humans (for reviews, see References 107,123, 124). Subchronic exposure studies in rodents and other animals such as cats have been used to identify and study the mechanism of action of neurotoxic chemicals which produce paralysis and behavioral changes in exposed animals. Studies are currently underway to evaluate the relative sensitivities of behavioral tests and morphological assays of peripheral and central nervous system axon morphology for detecting the earliest signs of chemically induced neuropathies. " ... 

Hussain, M.. and Oloffs, P. (1979). Neurotoxic effects of leptophos (RiosvelR) in chickens and rats following chronic low-level feeding. J. Environ. Sci. Health B 14, 367-382. 

Although maximum residue limits of leptophos were considered to be insufficient to be of toxicological importance the estimates of potential formulator/applicator exposure resulted in the deregistration of this compound, because of the potential to induce delayed neurotoxicity in humans. 

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