Organophosphorus Ester-Induced Chronic Neurotoxicity
MOHAMED B. ABOU-DONIA
Department of Pharmacology and Cancer Biology
Duke University Medical Center
Durham, North Carolina, USA
ABSTRACT.
Organophosphorus compounds are potent neurotoxic chemicals that are widely used in medicine, industry, and agriculture. The neurotoxicity of these chemicals has been
documented in accidental human poisoning, epidemiological studies, and animal models.
Organophosphorus compounds have 3 distinct neurotoxic actions. The primary action is the irreversible inhibition of acetylcholinesterase, resulting in the accumulation of acetylcholine and subsequent overstimulation of the nicotinic and muscarinic acetylcholine receptors, resulting in cholinergic effects. Another action of some of these compounds, arising from single or repeated exposure, is a delayed onset of ataxia, accompanied by a Wallerian-type degeneration of the axon and myelin in the most distal portion of the longest tracts in both the central and peripheral nervous systems, and is known as organophosphorus ester-induced delayed neurotoxicity (OPIDN). In addition, since the introduction and extensive use of synthetic organophosphorus compounds in agriculture and industry half a century ago, many studies have reported long-term, persistent, chronic neurotoxicity symptoms in individuals as a result of acute exposure to high doses that cause acute cholinergic toxicity, or from long-term, low-level, subclinical doses of these chemicals. The author attempts to define the neuronal disorder that results from organophosphorus ester-induced chronic neurotoxicity
(OPICN), which leads to long-term neurological and neurobehavioral deficits. Although the mechanisms of this neurodegenerative disorder have yet to be established, the sparse available data suggest that large toxic doses of organophosphorus compounds cause acute necrotic neuronal cell death in the brain, whereas sublethal or subclinical doses produce apoptotic neuronal cell death and involve oxidative stress.
KEY POINTS.
Industry only look at the first 2 not OPICN e.g House of Lords, CAA 2004 CAQ paper etc..
AVIATION CONNECTION.
Organophosphorus Ester-Induced Chronic Neurotoxicity (OPICN)
Various epidemiological studies have demonstrated that individuals exposed to a single large toxic dose, or to small subclinical doses, of organophosphorus compounds have developed a chronic neurotoxicity that persists for years after exposure and is distinct from both cholinergic and OPIDN effects. This disorder has been variously referred to in the literature by many differing terms but the review of the literature indicated that these studies describe a nervous system disorder induced by organophosphorus compounds which involves neuronal degeneration and subsequent neurological, neurobehavioral, and neuropsychological consequences.
Characteristics of OPICN.
OPICN is produced by exposure to large, acutely toxicor small subclinicaldoses of organophosphorus compounds. Clinical signs, which continue for a prolonged time ranging from weeks to years after exposure, consist of neurological and neurobehavioral abnormalities. Damage is present in both the PNS and CNS, with greater involvement of the latter. Within the brain, neuropathological lesions are seen in various regions, including the cortex, hippocampal formation, and cerebellum. The lesions are characterized by neuronal cell death resulting from early necrosis or delayed apoptosis. Neurological and neurobehavioral alterations are exacerbated by concurrent exposure to stress or to other chemicals that cause neuronal cell death or oxidative stress. Because CNS injury predominates, improvement is slow and complete recovery is unlikely.
Neurological and neurobehavioral alterations.
Although the symptoms of OPICN are a consequence of damage to both the PNS and CNS, they are related primarily to CNS injury and resultant neurological and neurobehavioral abnormalities. Studies on the effects of exposure to organophosphorus compounds over the past half century have shown that chronic neurological and neurobehavioral symptoms include headache, drowsiness, dizziness, anxiety, apathy, mental confusion, restlessness, labile emotions, anorexia, insomnia, lethargy, fatigue, inability to concentrate, memory deficits, depression, irritability, confusion, generalized weakness and tremors.Respiratory, circulatory, and skin problems may be present as well in cases of chronic toxicity.It should be noted that not every patient exhibits all of these symptoms.
SAME AS FOUND IN SICK CREWS.
Furthermore, OPICN induced by low-level inhalation of organophosphates present in jet engine lubricating oils and the hydraulic fluids of aircraft could explain the long-term neurologic deficits consistently reported by crewmembers and passengers, although organophosphate levels may have been too low to produce OPIDN.
CONCLUSION.
Herein we have described the long-term, persistent neurodegenerative disorder induced by exposure to organophosphorus compounds. We define this effect as organophosphorus ester-induced chronic neurotoxicity, or OPICN. Numerous cases documenting this disorder have been reported since the extensive use of these chemicals in industry and agriculture began more than 50 yr ago. Although largely characterized by chronic neurobehavioral alterations, OPICN involves other molecular, neurochemical, neurophysiological, neuropathological, neuropsychological, and neurological changes.
The term “neurotoxicity” encompasses all of these, and adequately describes this neurodegenerative disorder.