Review of health consequences from high-, intermediate- and low-level exposure to organophosphorus nerve agents

Brown, Mark A.; Brix, Kelley A.

doi:10.1002/(sici)1099-1263(199811/12)18:6<393::aid-jat528>3.0.co;2-0

Cited by 258 publications

(187 citation statements)

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“…[1][2][3][4][5][6][7][8][9][10][11] According to the World Health Organization, there are about 220,000 intoxications with organophosphorus pesticides throughout the world every year, leading to approximately 20,000 deaths. 1,[12][13][14] The most dangerous neurotoxic compounds are the chemical warfare agents soman (3), sarin (4), tabun (5) and VX (6) (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…In the AChE active site, a serine residue is responsible for the extraction of the acetyl group of acetylcholine, forming choline (9). If an organophosphorus compound (10) is present, phosphorylation of the serine of AChE may occur, thereby forming the inhibited enzyme (11). This may suffer the loss of an R + group (referred to as the aging process), leading to an irreversible form of the inhibited enzyme (12).…”

Section: Introductionmentioning

confidence: 99%

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The effect of neutral oximes on the reactivation of human acetylcholinesterase inhibited with paraoxon

Ribeiro¹,

Prates²,

Alves³

et al. 2012

J. Braz. Chem. Soc.

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Importantes agentes para defesa contra armas de guerra química são reativadores da acetilcolinesterase humana (huAChE) inibida por compostos organofosforados neurotóxicos (OP), e precisam de uma permeabilidade razoável pela barreira hematoencefálica (HB). Neste trabalho, oximas neutras, que penetram HB melhor do que as oximas catiônicas atualmente utilizadas como agentes de defesa, foram testadas como reativadores da huAChE inibida com paraoxon usando o método de Ellman modificado e pralidoxima (2-PAM) como padrão positivo. A oxima neutra mais ativa foi a 2-tiofenoaldoxima, que reativou 93% da huAChE inibida, sendo 12% mais eficiente do que a 2-PAM. Os resultados mostraram que oximas neutras simples possuem potencial para atuarem como antídotos para intoxicação com OPs neurotóxicos, sugerindo maior investigação no desenvolvimento de agentes de defesa neutros.Important defense agents against chemical warfare weapons, which are reactivators of human acetylcholinesterase (huAChE) inhibited by neurotoxic organophosphorus compounds (OP), need a reasonable permeation of the hematoencephalic barrier (HB). In this work, neutral oximes, which permeate HB better than the cationic oximes currently used as defense agents, were tested as reactivators of huAChE inhibited with paraoxon using the modified Ellman test with pralidoxime (2-PAM) as positive standard. The most active neutral oxime was (thiophen-2-yl)aldoxime, which reactivated 93% of the inhibited huAChE and was 12% more effective than 2-PAM. The results showed that simple neutral oximes have potential to function as antidotes for intoxication with neurotoxic OPs, suggesting further research on the development of neutral defense agents.Keywords: neutral oximes, huAChE reactivation, paraoxon, chemical warfare, (thiophen-2-yl)aldoxime IntroductionIntoxication with neurotoxic organophosphorus compounds is a serious problem caused by some pesticides used in agriculture, such as paraoxon (1) and malathion (2) ( Figure 1) and chemical warfare agents. [1][2][3][4][5][6][7][8][9][10][11] According to the World Health Organization, there are about 220,000 intoxications with organophosphorus pesticides throughout the world every year, leading to approximately 20,000 deaths. 1,[12][13][14] The most dangerous neurotoxic compounds are the chemical warfare agents soman (3), sarin (4), tabun (5) and VX (6) ( Figure 1). Though their use is prohibited by the United Nations, these agents have been employed as weapons by terrorist groups and by countries that did not sign the Chemical Weapon Convention administered by the Organization for the Prohibition of Chemical Weapons (OPCW).The principal target for the action of neurotoxic organophosphorus compounds is the enzyme acetylcholinesterase (AChE), a serine hydrolase that controls the nerve impulses at the cholinergic receptors in the central and peripheral nervous systems. 1,15-20 As shown in Ribeiro et al. 1217 Vol. 23, No. 7, 2012 Figure 2, the function of AChE (7) is the hydrolysis of the nerve impulse transmitter acetylcholine...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The effect of neutral oximes on the reactivation of human acetylcholinesterase inhibited with paraoxon

Ribeiro¹,

Prates²,

Alves³

et al. 2012

J. Braz. Chem. Soc.

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“…Their acute lethal action is attributed to inhibition of acetylcholinesterase by phosphorylation of its catalytic site (3). The second most important toxic effect of these compounds and some related pesticides, lubricants, and plasticizers is OP-induced delayed neuropathy (OPIDN) (4)(5)(6)(7). The principal causal agent for the Ͼ30,000 cases of human paralysis is tri-o-tolyl phosphate as an adulterant in beverages around 1930 and in cooking oil in 1959 (5-7), but concern continues because it is still a common component in commercial jet oils (8).…”

mentioning

confidence: 99%

Evidence that mouse brain neuropathy target esterase is a lysophospholipase

Quistad

Barlow²,

Winrow³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

122

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Neuropathy target esterase (NTE) is inhibited by several organophosphorus (OP) pesticides, chemical warfare agents, lubricants, and plasticizers, leading to OP-induced delayed neuropathy in people (>30,000 cases of human paralysis) and hens (the best animal model for this demyelinating disease). The active site region of NTE as a recombinant protein preferentially hydrolyzes lysolecithin, suggesting that this enzyme may be a type of lysophospholipase (LysoPLA) with lysolecithin as its physiological substrate. This hypothesis is tested here in mouse brain by replacing the phenyl valerate substrate of the standard NTE assay with lysolecithin for an ''NTE-LysoPLA'' assay with four important findings. First, NTE-LysoPLA activity, as the NTE activity, is 41-45% lower in Nte-haploinsufficient transgenic mice than in their wild-type littermates. Second, the potency of six delayed neurotoxicants or toxicants as in vitro inhibitors varies from IC 50 0.02 to 13,000 nM and is essentially the same for NTE-LysoPLA and NTE (r 2 ‫؍‬ 0.98). Third, the same six delayed toxicants administered i.p. to mice at multiple doses inhibit brain NTE-LysoPLA and NTE to the same extent (r 2 ‫؍‬ 0.90). Finally, their in vivo inhibition of brain NTELysoPLA generally correlates with delayed toxicity. Therefore, OP-induced delayed toxicity in mice, and possibly the hyperactivity associated with NTE deficiency, may be due to NTE-LysoPLA inhibition, leading to localized accumulation of lysolecithin, a known demyelinating agent and receptor-mediated signal transducer. This mouse model has some features in common with OP-induced delayed neuropathy in hens and people but differs in the neuropathological signs and apparently the requirement for NTE aging.

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“…Presently, more than 100 different OPC are used worldwide as insecticides [6]. The easy availability and innumerable benefits results in quite a number of intoxications [1,[6][7][8][9][10]. Use of pesticides is poorly regulated and often dangerous; their easy availability also makes them a common mode of self poisoning [1,8,11].…”

Section: Discussionmentioning

confidence: 99%

Audiological Assessment in Organophosphorus Compound Poisoning

Murthy¹,

Reddy

2012

Indian J Otolaryngol Head Neck Surg

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The aim of this prospective study design is to understand the audiological parameters in central and peripheral auditory pathway in organophosphorus compound (OPC) poisoning, within the setting of Tertiary care/ Medical College Hospital we studied Distortion Product Oto Acoustic Emission (DPOAE) and brain evoked response audiometry (BERA) in 25 patients with OPC poisoning with respiratory failure and 75 patients without respiratory failure. The results showed that DPOAE was absent in 17 patients with respiratory failure and 51 patients without respiratory failure. BERA showed significant prolongation in wave I, wave III and wave V latencies in both the groups.In conclusion, the current study has demonstrated significant changes in the auditory pathway both in peripheral and central with OPC exposure. The damage induced by these agents has been suggested as a combination of oto-and neurotoxicity with or without respiratory failure. Otolaryngologist should be alert to the toxic properties of OPC and conduct a comprehensive audiological assessment even in the conditions of deliberate poisoning.

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Review of health consequences from high-, intermediate- and low-level exposure to organophosphorus nerve agents

Cited by 258 publications

References 0 publications

The effect of neutral oximes on the reactivation of human acetylcholinesterase inhibited with paraoxon

The effect of neutral oximes on the reactivation of human acetylcholinesterase inhibited with paraoxon

Evidence that mouse brain neuropathy target esterase is a lysophospholipase

Audiological Assessment in Organophosphorus Compound Poisoning

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