OP compounds exert their toxicity by inhibiting the enzyme Acetylcholinesterase (AChE) that is responsible for the metabolism of the neurotransmitter Acetylcholine (ACh). The toxic symptoms of organophosphate poisoning (OPP) include muscarinic, nicotinic and central nervous system (CNS) effects. OP toxicity produces a broad range of well-characterized symptoms in central and peripheral nervous system, respiratory system, cardiovascular system, immune system, reproductive system, endocrine system etc.
Treatment of poisoned patients involves the administration of relevant antidotes as well as several decontamination procedures to ensure secondary contaminations.
The widespread use of OP pesticides is enhanced by their beneficial effects, on the other hand results in health hazards in humans as well as toxicity in aquatic and terrestrial life which has become a global problem today.
The development and the use of OP compounds were greater than ever before by the turn of the 21st century, a trend most likely to continue due to the scientific discoveries of new applications for those compounds. OPs are a group of compounds considered as inhibitors of AChE, the enzyme responsible for the termination of neurotransmitter ACh. OP compounds with strong AChE inhibiting potential are used as toxicants while those with weak potential are used as prophylactic agents against nerve agent poisoning or as therapeutic agents in glaucoma, myasthenia gravis and Alzheimer's disease (1). In addition, several other OPs are employed as flame retardants and there are many instances where OPs have been misused in intentional and malicious poisonings. Currently these AChE inhibiting OP compounds constitute the most widely used class of pesticides in industrialized as well as developing countries.
History of Organophosphate compounds.
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The earliest documented evidence regarding synthesis of OP compounds is the document presented to French Academy of Sciences by Phillipe de Clermont in 1854 explainig the synthesis of tetraethyl pyrophosphate. Lange and Kruger in 1932 synthesized dimethyl and diethyl phosphorofluoridates whose vapors caused dimness of vision and choking sensation. Gerhard Schrader, a German chemist involved in insecticide development synthesized his first insecticide known as parathion, which is still used worldwide. Prior to World War II, Ministry of Defense of Germany produced chemical warfare agents containing OPs which were subjected to a tremendous development to be used as nerve gases. In 1950s, United Kingdom and Soviet military produced highly potent, supertoxic nerve agents with proven success in wars (e.g. Sarin used in Iraq against Kurdish villages and in Japan in Tokyo subway attacks) and by dictators and terrorists (1).
After the World War II, numbers of OP derivatives were synthesized with species selectivity and less toxicity that could be used as insecticides/pesticides more safely. Malathion has been synthesized in 1950s, one of the most popular insecticides especially against mosquitoes and medflies for more than 50 years and considered as one of the safest. Although OP insecticides are definitely less toxic than the nerve agents/gases, clinically both resemble the same illness.
In addition to instances where essentially the purpose was to kill e.g. war and terrorism, every time an OP was used, associated people as well as animals evidently develop signs and symptoms of toxicity. The knowledge of autonomic pharmacology, especially the cholinergic system enabled to understand their mechanism of toxicity. In the early 1950s, several nucleophilic agents were developed such as hydroxylamine, hydroxamic acid and oximes, subsequently leading to antidotes for reactivation of inhibited AChE against OPs. For example, Pralidoxime proved a 1 million times greater potency than hydroxylamine in reactivation AChE, probably because it was developed with the thorough understanding of the chemistry of ACh, AChE and OPs (2).
Since the early 1980s, OPs have been used for multi purposes such as
Pesticides for crop and grain protection, indoor and around houses
In veterinary against ectoparasiticides and endoparasiticides
In human medicine in treating neurodegenerative diseases such as Alzheimer's disease while some are prescribed in myasthenia gravis, glaucoma and as prophylaxis to combat anticipated nerve agent poisoning.
As a result of a large number of researches carried out all over the world for the development and modifications of OPs, this is one the most widely used classes of chemicals in the world today.
Many OPs are extremely toxic and majority of them lack species selectivity and so, they constantly pose a threat to the environment, human and animal health, aquatic systems and wild life because of their global use.
Classification of Organophosphate compounds.
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The diversity of organophosphate compounds is enormous but different compounds have structural similarities within the classes. All OPs have a phosphorous (P) atom and a characteristic phosphoryl (P=O) or thiophosphoryl (P=S) bond. These are essentially the esters of phosphoric acid with varying combinations of O, C, S or N attached. However, the complex chemistry and confusing classification of OPs are arising due to different side chains attached to the P atom and the position of attachment.
There is no universally accepted classification system for OPs yet. At least 13 types of OP compounds exist which are the derivatives of phosphoric, phosphonic or phosphinic acid. The derivatives of phosphoric and phosphonic acids possess anti-ChE activity. Phosphorothioates (P=S) possess minimal or no anti-ChE activity until they are desulfurated to the analogous oxon. There exist some OP compounds that do not conform to the structural requirements but still exhibit anti-ChE activity. Moreover, not all the OPs exert anti-ChE activity and thus they are of low toxicity (e.g. merphos, glyphosate, glyphosinate) (1).
Organophosphate compounds are widely used as pesticides worldwide, of which the popularity may be partly due to the lack of residue persistence in the environment as well as in exposed individuals and less resistance development in insects (especially compared to organochlorines). Because of their widespread availability and extreme toxicity, OP pesticides are often encountered in accidental (environmental or occupational) and self-inflicted (suicide) poisonings in humans (and animals). Serious poisonings due to misuse of OP pesticides have been reported for more than five decades. Organophosphate warfare agents are known to be the most toxic out of all the compounds in this class of chemicals, whose oral lethal dose for man is estimated to be in the milligram range or even less (3). Despite the structural diversity, the mechanisms by which these compounds elicit their toxicity are identical and are majorly, if not entirely associated with the inhibition of ChE.
Organophosphate poisoning (OPP)
OPs get absorbed into the (human) body through all possible routes; skin, oral mucous membranes, conjunctiva, gastrointestinal tract and respiratory routes. OPs are generally highly lipid soluble. The onset, severity and duration of poisoning is determined by several factors including the degree and route of exposure, lipid solubility and rate of metabolism of the compound of interest and whether metabolism in the liver is required before the compound is active. The onset of clinical effects may be from 5min-24 hrs post exposure (3, 4).
Inadvertent OPP is resulting more frequently from their use in agriculture, usually by dermal absorption or by inhalatation during application or subsequent work in the field. Industrial poisoning in the OP synthesizing plants were common in early stages of their development but it is generally rare today as the manufacturing processes are being modified and are supervised by specialists. Even now, OPP is not rare in formulation plants where concentrated preparations are diluted with solvents, emulsifiers, dust etc and may involve several stages resulting in greater exposure. The incidence of ingestion in scientific and industrial research personals is often associated with new compounds of unknown toxicity. Poisoning in pilots who engaged in aerial applications of OPs has also been reported where even a mild symptom would result in aircraft accidents e.g. blurred vision, and even a small accident could expose the pilot to a concentrated preparation of OPs (3).
Suicidal OPP is considerably high in developing countries than in the West and appears to be increasing with the large availability and socio-cultural factors. The incidence of deliberate ingestion of OPs appears to be higher in young people and those with lower socio-economic status and usually lead to severe poisoning and poor outcomes. This will place a heavy burden on intensive care resources especially where those are scarce (5).
Mechanisms of organophosphate toxicity.
1. Inhibition of AChE.
The primary mechanism of action of OPs is the irreversible inhibition of AChE, an enzyme found in the CNS and the peripheral nervous system (PNS) whose function is to metabolize ACh, a neurotransmitter. OPs inactivate AChE by phosphorylating the serine hydroxyl group of its active site. In this phosphorylation, a new covalent bond is established between AChE and OP (step 1). This condensation reaction at the active site of AChE results in the formation of a trans intermediate complex (a) that partially hydrolyzes with the loss of a substituent group (Z) (step 2), resulting in a stable, phosphorylated and largely unreactive inhibited enzyme whose reactivation could be done at a very slow rate (1).* The formation of irreversibly inhibited enzyme is seen with many OP pesticides. The nature of the substituent groups at X, Y and Z determines the specificity for the enzyme.
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Novel OP insecticides have been introduced e.g. acephate, temephos, dichloryos which are less tenacious inhibitors of ChE as they dissociate from the enzyme more readily and spontaneously (1, 2, 6-9)
2.1.2. Pesticide-induced oxidative stress.
According to Banergee et al (1999) (10) free radicals play a major role in the toxicity of OP pesticides and environmental chemicals. It is assumed that OP compounds induce the oxidative stress by excessive generation of free radicals including reactive oxygen species and nitrogen species, altering the antioxidants and the scavenging system causing lipid peroxidation.
Several studies have demonstrated oxidative stress induced by OPs in rats and humans (10-14). Lipid peroxidation is also evident in rat brains and human erythrocytes (11-14). OP-induced seizures have been reported in association with oxidative stress. It has also been shown that the acute tubular necrosis that accompanies OP toxicity is related to reactive oxidative species and lipid peroxidation (15).
Clinical aspects of OP intoxication.
OP compounds exert their toxic effects by inhibiting the synaptic enzyme AChE responsible for the metabolism of the neurotransmitter ChE; accumulation of ChE in the synaptic gap leads to cholinergic crisis. Since the cholinergic system is widely distributed within both CNS and PNS, chemicals that inhibit AChE are known to produce a broad range of well-characterized symptoms.
Signs and symptoms of OPP include muscarinic, nicotinic and CNS effects, all of which can be attributed to the accumulation of ACh in the synapse leading to neural overstimulation (8).
Muscarinic effects are manifested by hypersensitivity of the parasympathetic system including miosis, bradycardia, excessive salivation, lacrimation, urination and defecation (abbreviated by the acronym SLUD), hypersecretion in digestive and bronchial glands and several other symptoms including nausea, pallor, abdominal cramps, vomiting and excessive bronchoconstriction. Nicotinic effects include muscular fasciculation, cramping and weakness, and in severe poisoning muscular paralysis. The severity of ensuing muscarinic and nicotinic symptoms is dose dependent and can result in death due to cardiovascular and respiratory collapse. CNS toxicity symptoms are vital including depression of respiration, seizure, unconsciousness, giddiness, headache and finally paralysis of the respiratory centre leading to death of the animal (7, 9, 16). Patients are commonly admitted with miosis, fasciculations, pulmonary oedema and froth at the mouth due to manifestations of above three types of cholinergic poisoning.
Electrophysiological studies in suicidal patients with OPP have reported that patients often developed muscle weakness of variable severity owing to depolarization block at nicotinic receptor. During such paralysis, nerve conduction velocity and distal latencies were observed to be normal even in severely paralyzed patients, but the amplitude of the compound action potential was tended to be lower in those more severely affected (17).
PNS and CNS effects and neurotoxicity.
Inhibition of AChE results in persistent activation of cholinergic receptors on postsynaptic cells leading to functional signs and symtopms of cholinergic toxicity. Many of the classical signs associated with OPP are peripheral in nature as described under muscarinic effects, a consequence of the overstimulation of muscarinic receptors in the PNS. Other common signs include nicotinic effects resulting from the overstimulation of nicotinic receptors in PNS. The most relevant effect of OPP in PNS is OP induced delayed polyneuropathy (OPIDN).
Inhibition of AChE by OPs elicit profound alterations in CNS result in several severe and lethal intoxications out of which respiratory depression found to be the most important. Neurobehavioral alterations are also commonly encountered as a consequence. Although the toxic effects are commonly elicited through AChE inhibition, interactions of OPs with other macromolecules in the CNS have been shown to modify cholinergic toxicity or affect other signaling cascades.
Several pathophysiologic studies have concluded that OPP in humans produces three well defined neurologic paralytic syndromes; Type I, Type II and Type III (17, 18).
Type I: Acute peripheral and central cholinergic block.
The acute syndrome involves paralysis secondary to persistent depolarization at the neuromuscular junction (NMJ) due to the inhibition of AChE by the OP and direct actions at the synapse involving a variety of chemosensitive receptor ion channels. Central and peripheral cholinergic effects at muscarinic receptors include bilateral pyramidal signs and impairment of consciousness and miosis. Type I symptoms are usually present on admission and responding promptly to atropine therapy. This initial life threatening phase often requires the intensive care management.
Type II: Intermediate syndrome.
This is caused by the excess of ACh at nicotinic receptors and appears 12-72 hrs after poisoning and lasts up to 4-18 days. Defects in neuromuscular transmission and toxin-induced muscular instability are key features of Type II syndrome. Patients develop progressive and often severe weaknesses of which symptoms include cranial nerve palsies, proximal muscle weakness and respiratory muscle weakness therefore patients often require respiratory support. Intermediate syndrome can be further complicated by infections and cardiac arrhythmias.
Type III: OPIDN.
OPIDN occurs 1-3 weeks after exposure and is likely to become more frequent as a patient survived from severe over dosage of certain OPs. This is characterized by a distal degeneration of long and large-diameter motor and sensory axons of both peripheral nerves and spinal cord where symptoms include distal muscle weakness with relative sparing of the neck muscle, cranial nerves, and proximal muscle groups. Neurophysiologic effects associated with chronic OP intoxication include impaired memory, confusion, irritability, lethargy and psychosis. Recovery from OPIDN can take up to 12 months. However, patients sometimes may not exhibit these well defined neurologic syndromes (2, 17, 18).
Cardiac complications are often seen in OPP which may be serious and often fatal. OPs cause histopathological changes in cardiac tissue and, excessive ingestion can seriously affect cardiac function. In severe OP intoxications, the heart goes into ventricular fibrillation (VF). OP deposition in the heart depends on dose and route of administration and spatially heterogeneous. The damage to the tissue is focal, with pericapillary hemorrhage, micronecrosis, and patchy fibrosis leading to decreased conduction and altered reploarization dynamics. However, relatively little work has been done on the alteration of cardiac tissue by OPs and thus the extent, frequency and pathogenesis of the cardiac toxicity from OPs have not been clearly defined.
Several research findings have reported myocardial necrosis from OP intoxication such as ultrastructural morphological changes including swollen forms and fragmentation or lysis of cristae. Studies have revealed the formation of amorphous dense bodies in mitochondria that assumed to be derived from local lipids, disabling the ATP production subsequently leading to a disastrous energy deficit. Lesions in the presence of OPs are primarily seen in the left ventricular region, which is believed to occur due to the blockage of several potassium channels.
Cardiac complications of OP intoxication are lethal but potentially preventable if recognized early and treated adequately (19, 20, 21).
Respiratory and pulmonary toxicity.
The lungs are a major organ system of entry into the body therefore possibility of ingestion of OPs via lungs is extremely high. Respiratory and pulmonary toxicity often associates with direct inhalation and also indirect effects are seen with all aspects of respiration through systemic toxicity as well.
The lungs are one of the first organs affected following contact with aerosols and vapors of OPs. Lung toxicity by these compounds is due to parasympathetic muscarinic effects leading to increased glandular secretions throughout the respiratory tract and alveoli, bronchoconstriction from contraction of airway smooth muscle, nicotinic effects on respiratory muscles in the thorax and accessory muscles of the neck causing labored breathing and eventually flaccid paralysis, and central effects resulting in a decrease in respiratory drive.
Anyway, the types of respiratory symptoms described by patients seem to be not consistent including coughing, wheezing, increased exertional dyspnea, dyspnea at rest, inability to breathe deeply, and a sensation of pressure in the throat/chest. Rhinnorrhea is also considered as part of pulmonary toxicity which is shown to be followed by hyperemia of the nasal mucosa. There are no consistent patterns observed in those symptoms (22, 23).
This is one of the major concerns of occupational health and safety in many industries where a lot of research workers have revealed androgenic as well as estrogenic effects of OPs. Both human health and ecological wellbeing are affected by OPs where reproductive tract cancers, reduced fertility and abnormal sexual development would possibly result. Many OPs are thought to mimic or otherwise disrupt the estrogen/androgen balance in the body by binding to the receptors of those hormones during fetal and neonatal development and thus are called 'endocrine disruptors' or 'gender benders'. Reproductive toxicity is expressed in terms of alterations in sexual behavior and performance, infertility and/or abortions. Exposure to chemicals may alter male and female reproductive systems and adversely affect the onset of puberty, gamete production and transport, normality of the reproductive cycle, sexual behavior or modifications in other functions that depend on the integrity of both male and female reproductive systems (24).
Even though very little direct information is available on OP toxicity in placenta, studies on OP administration during pregnancy done on experimental animals have shown fetal outcomes and sometimes residues of OPs in fetal tissues. The interest in exploring placental toxicity is enhanced by the fact that placenta is merely an entry but not a barrier therefore if mother ingests an OP (or any AChE inhibitor) accidentally or purposely, there is a high degree of fetal exposure to those chemicals. Physicochemical properties of the toxicant and type of the placenta are two key factors involved in transplacental transfer of toxicants/OPs. Because of the comparatively low molecular weight, OPs are not restricted from reaching the fetus. Chemical properties such as lipophilicity, polarity and degree of ionization also may affect the rate of placental transfer. In higher animals, complex and multilayered placenta usually makes it more difficult for OPs and other toxicants to gain access to the fetus compared to simpler choriovitelline or chorioallantoic type placenta. Several other factors including maternal-fetal chemical gradient, uterine and umbilical blood flow and protein binding may affect the rate as well as the extent of transplacental transfer and maternal-fetal equilibrium of an OP.
In general, elucidating the role of the placenta in contributing to developmental effects and fetotoxicity is considerably important. Although there are huge gaps in the existing knowledge of the placenta and pesticides, a variety of tools are available to obtain useful information for assessing the risk of pesticides to the placenta and developing fetus (25, 26).
A number of studies suggest that OPs/antiAChE chemicals are immunotoxic. However, due to various compounds analyzed according to various testing protocols that have given variable results even with the same compound, comparison of data is difficult. Anyway, overall evaluation of available information shows that both suppression and enhancement of immunity are mediated by OPs. Although immunotoxic effects exist, since they are observed at systemically toxic doses, their relevance to environmental exposure of OPs is quite less. Systemic toxicity would likely to alter the immune functions as a result of general stress (27, 28).
Diagnosis and treatment.
OPs exert their toxic effects by inhibiting AChE and subsequent accumulation of ACh in blood enabling blood ACh measurements to be used as an indicator of OPP. However, serum ACh level has never been validated and a connection between serum ACh activity and the severity of OPP has not been well established (7). Novel analytical methods including immunoassays (especially ELISA), extraction followed by gas chromatography integrated mass spectrometry (GC/MS) are employed to qualify and quantify OP intoxication.
The discovery of the nature of the biochemical lesion in OPP has permitted drug design to repair the particular lesion. OPs are lethal as they inactivate AChEs by phosphorylation of the enzyme's active centre. Based on that, two rational lines of treatments were proposed.
To find some compound that could be phosphorylated as rapidly as the enzyme and which if introduced into the body, would protect the enzyme from inhibition by competing with it for the OP or
To find a compound which would restore the activity of the inhibited enzyme by dephosphorylating it.
In both cases essentially the same type of compound is needed processing a high intrinsic reactivity with OP compound with the inhibitor itself or the phosphorylated enzyme. Several compounds have been identified with either or both of these properties out of which pyridine-2-aldoxime methiodide (PAM) and its corresponding methanesulphonate (P2S) introduced in 1950s are among the most successful in reactivating and treating poisoned subjects by far. The muscarinic antagonist atropine is used in high doses, diazepam is used for controlling muscle twitching and convulsions whereas the antidote pralidoxime acts by splitting the OP-AChE bond and regenerating acive AChE (2, 8, 9).
Decontamination is one of the most important procedures to follow after an OPP is identified. OPP is internal until the patient vomited and from then on can be regarded as a chemical spill. With that understanding, this could have been anticipated to prevent further dermal and/or inhalation contact. Furthermore, removal of clothes, thorough washing of patient's skin with soap containing 30% ethanol (high pH hydrolyzes OP in aqueous solutions) and plenty of warm water, isolation of the ventilation system of the unit from that of the main hospital if possible are recommended in patient management to prevent further patient contamination and secondary contamination of staff. Once effective dermal and gut decontaminations are achieved and adequate ventilation has been established, the patient is considered safe from causing secondary contamination (29).
Effects on aquatic and terrestrial life.
Among the global problems arisen due to the extensive use of OP compounds (primarily as pesticides), contamination of aquatic environment is very important. The possible routes of contamination include surface runoff and sediment transport from treated soil, industrial effluents, direct application to control pests inhabiting water, spray drift from normal agricultural operations and municipal waste discharge. Pesticides in general are toxic to many non-target organisms hence cause ecological imbalance by indiscriminate killing of fish, aquatic insects, mollusks, worms etc. The distribution of pesticides in water influences biological uptake thus will lead to accumulation in various levels in food chains.
Toxicity of OPs has been observed in terrestrial vertebrates and some birds in US (30), and further findings revealed that most of such incidents are consequences of pesticide misuse. Research findings indicate an inhibition of red blood cell AChE with dimethoxy substituted compounds.
Use of OPs mainly as pesticides has become indispensable due to beneficial effects they have on agriculture but at the same time has given rise to various health hazards in humans as well as in animals from accidental or intentional ingestion.
"All pesticides possess an inherent degree of toxicity to some living organism; otherwise they would be of no practical use and there's no such thing as a completely safe pesticide"- paradox of pesticides by Ecobichon (31).