Neurotoxicity cholinesterase

The neurotoxic cholinesterase inhibitors developed for chemical warfare, also used by terrorists, can kill wildlife species. Birds and other wildlife are well-known nontarget species for insecticides through intentional poisonings and contaminated seeds, water, forage, and... 

No NOAELs or LOAELs were identified for toxic effects in humans after inhalation exposure to organophosphate ester hydraulic fluids. Reliable NOAELs and LOAELs for acute inhalation exposure are restricted to 4-hour NOAELs for systemic effects in rats exposed to Fyrquel 220 or Durad MP280 and 4-hour LOAELs for mild lethargy in rats exposed to Durad MP280 and Fyrquel 220 (Gaworski et al. 1986). The study identifying these NOAEL and LOAEL values did not measure cholinesterase inhibition, did not allow sufficient follow-up time for the development of delayed neurotoxic effects, and used a... 

The inhibition of two cholinesterase activities in blood can also be used to confirm exposure to certain organophosphate ester compounds. Red blood cell acetylcholinesterase is the same cholinesterase found in the gray matter of the central nervous system and motor endplates of sympathetic ganglia. Synonyms for this enzyme include specific cholinesterase, true cholinesterase, and E-type cholinesterase. Plasma cholinesterase is a distinct enzyme found in intestinal mucosa, liver, plasma, and white matter of the central nervous system. Synonyms for this enzyme include nonspecific cholinesterase, pseudocholinesterase, butyrylcholinesterase, and S-type cholinesterase (Evans 1986). Nonspecific cholinesterase is thought to be a very poor indicator of neurotoxic effects. 

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). 

Most insecticides, especially the organophosphate group, cause neurotoxicity as their major mode of action. Assessment of the neurotoxicity includes neurochemical endpoints such as cholinesterase (including acetylcholinesterase, which is the major neurotransmitter in vertebrates such as fish, and other enzymes such as butyrylcholinesterase) inhibition and behavioral endpoints such as swimming speed [79]. Studies done in rats show the neurotoxic action of insecticides such as dimethoate, methyl parathion, dichlorvos, ethyl parathion or propoxur after a prolonged exposure [80,81]. 

SPMD sample extracts, e.g., certain organochlorine pesticides (OCPs), are known to inhibit cholinesterase activity. Therefore, these results were not unexpected. However, it was surprising that a similar response was not observed with brain cholinesterase activity. It is possible that brain cells can more readily metabolize the chemicals, that the chemicals did not pass the brain blood barrier or that the effects occurred earlier in the exposure period, effectively allowing the activity to recover. Considering the numerous neurotoxic chemicals potentially entering aquatic ecosystems or present as airborne vapor phase chemicals, the neurotoxic mode of action related to exposure to contaminants is of increasing interest. Evidence presented in this work demonstrate that SPMDs concentrate members of this class of toxicants. 

Anger, W. K. (1981). Effects of carbaiyl on variable interval response rates in rats. Neurobehavioral Toxicology 2 21-24. Bear, D. M. (1986). Aggression in cat and human precipitated by a cholinesterase inhibitor. Psychosomatics 27 535-536. Branch, R. A. (1986). Is carbaryl as safe as its reputation Does it have a potential for causing chronic neurotoxicity in humans American Journal cf Medicine 80 659-664. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

Sheets LP, Hamilton BF, Sangha GK, et al Subchronic neurotoxicity screening studies with six organophosphate insecticides an assessment of behavior and morphology relative to cholinesterase inhibition. Fundam Appl Tox/ro/35(1) 101-19, 1997... 

Acetyl cholinesterase activity AChE,. brain Neurotoxic parameter Organophosphate and carbamate pesticides Brain tissue 13-15... 

Sturm, A., Da Silva de Assis, H.C., Hansen, P.D. (1999). Cholinesterases of marine teleost fish enzymological characterization and potential use in the monitoring of neurotoxic contamination. Marine Environmental Research, 47 ... 

Studies on the scaleless chicken are underway examining its suitability as a model for assessing toxicity of organophosphates. The first compound selected for field trials was the defoliant DEF (S,S,S-tributylphosphorotrithioate) used during the harvesting of cotton in California and Arizona in the fall (October-November) when air movements are frequently restricted by inversions. DEF has been the subject of sufficient complaints to place it on the pre-RPAR list, although there are no reports of acute or delayed neurotoxicity in humans when it and related chemicals are used according to recommendations. It both inhibits cholinesterases and causes delayed neurotoxicity in hens (3,6). 

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