PRINCIPLES OF TOXICOLOGY - Biology East Borneo

15.1 ORGANOPHOSPHATE AND CARBAMATE INSECTICIDES 349ing), and Salivation. Signs and symptoms associated with overexposure to organophosphates andcarbamate compounds generally do not occur unless acetylcholinesterase activity is approximately 50percent or less of normal activity.Signs and symptoms in cases of mild to moderate organophosphate intoxication typically resolvewithin days to weeks following exposure. In cases of severe organophosphate intoxication, it can be3 months or so before cholinesterase red blood cell levels return to normal. Death from organophosphateintoxication is usually due to respiratory failure from depression of the respiratory center in thebrain, paralysis of the respiratory muscles, and excessive bronchial secretions, pulmonary edema, andbronchoconstriction. Death in individuals with acute organophosphate intoxication that are untreatedtypically occur within the first 24 h, and within 10 days in treated individuals. If there is no anoxia,complete recovery will occur, in general, within about 10 days after the exposure incident.Carbamate intoxication presents similar to that of organophosphate intoxication. Cases of carbamateintoxication resolve much more quickly than cases of organophosphate overexposure, due tothe rapid reversal of acetylcholinesterase enzyme as well as to the rapid biotransformation in vivo.Chronic Effects of Organophosphate and Carbamate InsecticidesIn general, the main reported chronic effect that may result from exposure to organophosphateinsecticides is delayed neuropathy. Organophosphate-induced delayed neuropathy has been associatedwith exposure to only a few organophosphate compounds, with cases occurring almost exclusively atnear-lethal exposure levels. Studies of individuals involved with the handling or formulation oforganophosphate compounds (e.g., chlorpyrifos) have not shown permanent adverse health effects.No permanent effects generally result from carbamate intoxication; delayed neuropathy does not occuras a result of carbamate poisoning (see discussion below).Organophosphate-Induced Delayed NeuropathyA few of the organophosphates have been associated with the development of a delayed predominantlymotor peripheral neuropathy, termed organophosphate-induced delayed neuropathy (OPIDN). In theUnited States in the 1930s, individuals developed OPIDN, also called “ginger jake” paralysis afterconsuming ginger liquor contaminated with triorthyl cresyl phosphate (TOCP). Other outbreaks ofOPIDN have occurred in relation to the consumption of cooking oil contaminated with TOCP.Organophosphates that have been associated with OPIDN include TOCP, mipafox, trichlorphon,leptophos, and methamidophos. It should be pointed out that only a few of the organophosphatecompounds actually are capable of causing OPIDN.The development of OPIDN is not physiologically related to cholinesterase inhibition. The nervelesion in OPIDN is that of a distal symmetric predominantly motor polyneuropathy of the long,large-diameter axons (the short, small diameter nerves appear to be spared) in the peripheral nerves.OPIDN, as its name suggests, has a delayed onset of approximately 1–3 weeks following an acutelife-threatening exposure to an organophosphate capable of causing delayed neuropathy. The initialcomplaints of OPIDN include cramping of the calves with numbness and tingling in the feet and thenlater in the hands. Next, weakness develops in the lower limbs. Bilateral foot drop and wrist drop maydevelop, and there are usually absent or normal reflexes. A high-stepping gait has also been describedin individuals with OPIDN. There also may be motor weakness involving the limbs and motor nerveconduction studies may show abnormalities.The current theory as to the cause of OPIDN involves a two-step process that occurs in the nervoussystem. First, it is thought that phosphorylation of a target protein in the nervous system is required.This enzyme is known as neuropathy target esterase (NTE), formerly known as neurotoxic esterase.The biological action of NTE in the body is not known. The second, and essential, step leading toOPIDN is thought to be the transformation, or “aging,” of the enzyme. This “aging” process involvescleavage of an R group from phosphorous, resulting in a negatively charged residue attached to theactive site of the enzyme. It appears that compounds that are capable of inhibiting NTE and aging can