OP-induced delayed neuropathy

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). 

OP compounds that produce delayed neurotoxic effects are esters of phosphtsrus-containing acid.s. More than 35 years ago, tri-o-cresyl phosphate (TOCP) was known to produce delayed neurotoxic effects in humans and chickens characterized by ataxia and weakness of the limbs, developing 10-14 day.s after exposure (John,son. 1969). This syndrome is called OP-induced delayed neuropathy (OPIDN). TOCP and certain other compounds have minimal or no anti-AChE... 

It is known that human exposure to organophosphorus compounds can result in a variety of acute toxic effects. These arise primarily as a result of the inhibition of acetylcholinesterase. Signs of acute toxicity are due to effects on the central nervous system (anxiety, ataxia, hypotension), to muscarinic effects (wheezing, cough, rhinitis) and to nicotinic effects (muscle weakness, mydriasis and tachycardia). Other acute effects include chest tightness, abdominal cramps, confusion and convulsions. With some organophosphorus compounds, a specific syndrome may develop. This is delayed peripheral neuropathy or OP-induced delayed neuropathy (OPIDN). (For a more detailed discussion on the toxicity of organophosphorus compounds see Chapter 10.)... 

Following exposure to certain OP pesticide compounds, a fiuther long-term complication has been described. This is OP-induced delayed neuropathy (OPIDN) which can appear between 1 and 3 weeks post-exposure. This peripheral neuropathy is characterised by incoordination, ataxia, spasticity and flaccid muscle paralysis. Unlike IMS, the condition begins in the lower Umbs and then spreads to the upper limbs. In severe cases, the result may be permanent quadriplegia. 

AChEs and BuChEs are specialized carboxylic ester hydrolases that preferentially hydrolyze choline esters. They are classed among the B-esterases, enzymes that are inhibited by OPs. Another B-esterase is neuropathy target esterase (NTE), an enzyme associated with organophosphate-induced delayed neuropathy (OPIDN). Enzymes that actively hydrolyze OPs are known as A-esterases. They provide an important route of detoxification. Examples are par-aoxonase and DEPase (Table 1). The tertiary structure and amino acid sequences of several AChEs and BuChEs have been elucidated. 

Many individuals have genetic susceptibility to certain chemicals (Calabrese 1978). The influence of these genetic differences likely produces sub- and supersensitivity to OP insecticides and warfare agents (Russell and Overstreet 1987). Several enzymes with variations or polymorphisms control sensitivity to OPs red blood cell acetylcholinesterase, serum cholinesterase or pseudocholinesterase, lymphocyte neuropathy target esterase or platelet neuropathy target esterase (NTE), serum paroxonase, butyrylcholinesterase, and serum arylesterase (Costa et al. 1999 LaDu 1988 Li et al. 1993 Mutch et al. 1992). Inhibition of red blood cell acetylcholinesterase, in both the central and the peripheral nervous systems, produces acute symptoms (Mutch et al. 1992). Paroxonase and arylesterase further modify the response (LaDu 1988 Li et al. 1993). Variant, inactive butyrylcho-linesterases increase sensitivity to OPs (Lockridge and Masson 2000 Schwarz et al. 1995). OP-induced delayed polyneuropathy results... 

Exposure to insecticides also carries high risk for posttraumatic stress disorder. Insecticides exacerbate preexisting mental conditions, and atropine treatment of OP poisoning may induce psychotic symptoms. Incomplete assessment may overlook organophosphate-induced delayed neuropathy presenting as fatigue or weakness. 

Organophosphate-induced delayed neuropathy is unrelated to the anticholinesterase (anti-ChE) effects of OP agents because many highly potent cholinergic OPs do not cause neuropathy, and other OP compounds such a.s tri-o-cresyl phosphate (which is not used as a pesticide) have only weak anti-ChE activity but are powerful inducers of neuropathy. The enzyme involved in organo-phosphatc-induced delayed neuropathy is neuropathy target esterase—lysophospholipase (Lush et al 1998 ... 

Organophosphate Induced Delayed Neuropathy (OPIDN) and other long-term problems of organophosphorus ester (OP) agricultural chemicals pose special problems for risk assessment. Procedures have been developed over the years to evaluate the dangers from acute exposures to OPs, but the Insidious effects of repeated exposures to toxic chemicals are more difficult to anticipate and to detect. 

Some OP compounds induce delayed neurotoxic effects ("delayed neuropathy") after acute poisoning. This delayed neurotoxic action is independent of cholinesterase inhibition but related to phosphorylation of a specific esterasic enzyme in the nervous tissue, called "neurotoxic esterase" or "neuropathy target esterase" (NTE) (Johnson, 1982). NTE is present in the nervous tissue, liver lymphocytes, platelets, and other tissues, but its physiological function is unknown. There is a rather large inter-individual variation of lymphocyte and platelet NTE activity (Table 2). 

OP pesticides-induced delayed peripheral neuropathy can be caused by nerve agents only at doses many times greater than the LD50 (Davis et al, 1960)... 

The term delayed neurotoxicity may be used to describe any type of toxicity to the nervous system involving a delay between the precipitating chemical exposure and the appearance of neurological signs or symptoms. However, this designation usually refers to organophosphorus (OP) compound-induced delayed neurotoxicity (or delayed neuropathy) (OPIDN), also known as OP compound-induced delayed polyneuropathy (OPIDP). 

OP insecticide-induced intermediate syndrome (IMS) was reported for the first time in human patients in Sri Lanka in 1987 (Senanayake and Karalliede, 1987). Since then, this syndrome has been diagnosed in OP-poisoned patients in South Africa (1989), Turkey (1990), Belgium (1992), the United States (1992), Venezuela (1998), France (2000), and elsewhere. IMS is usually observed in individuals who have ingested a massive dose of an OP insecticide either accidentally or in a suicide attempt. IMS is clearly a separate clinical entity from acute toxicity and delayed neuropathy. A similar syndrome has also been observed in dogs and cats poisoned maliciously or accidentally with massive dosc.s of certain OPs. OPs that are known to cause IMS include bromophos, chlorpyrifos, diazinon, dicrotophos, dimethoatc, fenthion, malathion, merphos, methamidophos, methyl parathion, monocrotophos, omethoate, parathion, phosmet, and trichlorfon. These compounds and IMS are discussed further in Chapter 26. 

Early high-toxicity pesticides such as TEPP and parathion have now fallen out of use. Organophosphorus pesticides (and in some cases other phosphate esters such as tricresyl phosphate) are now believed to produce several responses in humans. Acute symptoms can appear within hours of exposure, intermediate syndromes within days, and a delayed response which may take months or even years to develop. The latter is known as OP-induced neuropathy (OPIDN) and is difficult to treat and may be irreversible. 

---