INTRODUCTION
Organophosphates are chemicals that are produced by a process of esterification between alcohol and phosphoric acids.[1] They are widely used in agriculture as well as in buildings to control pests.[2] Organophosphates form the basis from which most pesticides and insecticides are produced.[3]
The chemical structure is composed of a phosphate group which forms the basic structural framework,[4] as shown in Figure 1.
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Figure 1: Chemical structure of organophosphate[5]
CLASSIFICATION OF ORGANOPHOSPHATES
Examples of organophosphates classified based on structure include phosphates, phosphonates, phosphinates, and phosphorothioates (S=), phosphonothioates (S=), phosphorothioates (S substituted), phosphonothioates (S substituted), phosphorodithioates, phosphorotrithioates, and phosphoramidothioates.[5] As shown in Figure 2.
Figure 2: Structural classification of organophosphates[5]
HISTORY OF ORGANOPHOSPHATES
As early as the 19th century, there has been a synthesis of organophosphate compounds.[6] Gerhard Schrader, a German chemist at company IG Farben, synthesized organophosphate, which was used as a chemical agent of war,[7] although he initially aimed his work in developing insecticides. In 1936, he synthesized a very toxic compound known as ethyl-N, N-dimethylphosphoramidocyanidate (tabun), and in 1937, isopropyl methylphosphonofluoridate (sarin) was synthesized.[8]
The synthesis of these compounds caused the German military to apply them in warfare thereby directing Gerhard Schrader research from an insecticidal to a warfare agent.[9] Although an inexpensive compound knows as dichlorodiphenyltrichloroethane an organochlorine was synthesized in 1939 to be used as an insecticide,[10] they were found to bio accumulate unlike organophosphates which do not accumulate in the environment and are rapidly hydrolyzed when exposed to air, sunlight, and soil.[11] This led to many European countries as well as the USA banning the use of organochlorines.[12] Organophosphate use as a pesticides was then exploited and therefore became widely used in controlling agricultural and household pests.[13]
USES OF ORGANOPHOSPHATES
There are numerous organophosphate chemicals which are widely used as insecticides and pesticides in various parts of the world.[1415] Organophosphate pesticides such as terbufos, chlorpyrifos, diazinon, parathion among others are generally used as an agricultural and a household insecticide.[16] Some organophosphate chemicals such as glyphosate and tribufos are used as herbicides, while trichlorfon is used as an anthelmintic agent.[17]
MODE OF ACTION OF ORGANOPHOSPHATES
Organophosphates generally by inhibiting acetyl cholinesterase enzyme which hydrolysis acetylcholine and excitatory neurotransmitter in vertebrates and insets.[18] As shown in Figure 3.
Figure 3: Inhibition of acetyl cholinesterase by organophosphates[18]
The acetylcholinesterase inhibition and consequent synaptic junction accumulation of acetylcholine, results in a continuous stimulation of the postsynaptic tissue.[19]
When inhibited, acetyl cholinesterase is reactivated rapidly depending on the chemical structure of the organophosphate used, and because of this rapid or spontaneous reactivation, organophosphates are therefore classified into reversible and no-reversible acetyl cholinesterase inhibitors.[20] The inhibition of acetyl cholinesterase by organophosphates possessing dimethyl-and diethyl phosphate structure is most of the time not.[2122] For organophosphate chemical warfare agents such as tabun and sarin, there is usually no rapid/spontaneous acetylcholine reactivation due to their branched radicals.[9]
ORGANOPHOSPHATE TOXICITY
Widely used globally, organophosphate pesticide exposure poorly control especially in cases when personal protective equipment are not used.[23]
There are however two types of toxicity: acute and chronic organophosphate toxicity.
Acute organophosphate toxicity
Even though it was widely claimed that organophosphate has an advantage over the more popular organochlorines, it has, however, been found that organophosphate causes far greater acute toxicity and are as such, far more hazardous than the later.[24] Suicide attempts are one of the consequences of the classical syndromes of acute toxicity in humans exposed to organophosphate.[2526] There are three different forms in which acute toxicity from organophosphates can be expressed, and these are cholinergic syndrome, intermediate syndrome (IMS), and delayed polyneuropathy.[27]
Cholinergic syndrome
This occurs when acetyl cholinesterase is inhibited following accumulations of acetylcholine at synaptic and neuromuscular junctions in the cholinergic pathways, which results in the overstimulation of the postsynaptic muscarinic and nicotinic receptors. The physiological actions of these receptors are therefore said to be exaggerated.[28] Cholinergic syndrome being a consequence of organophosphate exposure, within minutes or hours after exposure.[26] Some of the symptoms of cholinergic syndrome are sweating, lacrimation and salivation, respiratory difficulties and cough, miosis, dyspnea, wheezing, bradycardia, cyanosis, nausea, vomiting, involuntary defecation and urination, headache, dizziness, confusion, and ataxia among others.[29] Some patients who survive the first day may experience or exhibit personality changes, psychotic episodes, paranoia, and existing psychiatric problems may be exacerbated. There could be hallucinations and nightmares as well as attention and memory disorders.[3031] It has also been shown that death caused by organophosphate poisoning could be centrally mediated,[32] as death would occur because of respiratory failure (resulting from the depression of the respiratory center of the brain and respiratory muscle paralysis).[3133]
Cholinergic syndrome is usually diagnosed based on the history, situation regarding exposure, clinical presentation, and laboratory tests are used to confirm diagnosis by assaying blood acetyl cholinesterase or plasma/serum cholinesterase activity.[34]
Intermediate syndrome
This was first described by Senanayake and Karalliedde[35] as a distinct clinical entity. Intermediate syndrome is so termed since it starts around 24–96hrs after initial exposure[36] and could last from 5 to 18 days and in very rare cases can last to 21 days according to Das et al.,[37]
The characteristics of IMS are acute respiratory insufficiency as a result of the respiratory muscles being paralyzed.[3738] Other symptoms of IMS are weakness of neck flexion, weakness of the proximal limb muscle that manifests as shoulder abduction, and hip flexion weaknesses.[3639]
Usually followed organophosphate metabolites excretion in urine and a marked reduction in cholinesterase level, IMS could be said to either be a decline in the number of functional cholinergic receptors at postjunctional membrane or a failure in the release of acetylcholine.[31] Diethyl organophosphates are less likely to produce IMS than dimethyl organophosphates.[40]
Organophosphate-induced delayed polyneuropathy
Organophosphateinduced delayed polyneuropathy (OPIDP) is rare and manifests between 10 and 20 days after a single exposure to organophosphate insecticide.[31] It is basically an axonopathy of the distal sensory-motor where the long axons of the central and peripheral nervous systems are degenerated which may result in paralysis about 2 or more weeks after organophosphate exposure.[41] Lotti and Moretto[42] reported organophosphate induced delayed polyneuropathy outbreaks in humans in some countries such as Morocco and the USA while it has also been observed in some animals such as sheep and chickens[43] and Husain[4] reported it in some experimental rodents. Parathion, leptophos, methamidophos, malathion, and some other organophosphates have also been found to induce OPIDP.[44]
Although the mechanism in which OPIDP develops is not fully understood, it is however thought that target esterase activity in the nervous system is gradually lost thereby membrane phospholipid and the functions of the endoplasmic reticulum which includes axonal transpots as well the interaction between glial and axons is supposedly disrupted.[445] It has however been observed that OPIDP may be caused by exposure to organophosphate compounds in large toxic doses, which may result in acute neuronal cell death in the brain.[46] Masoud and Sandhir[47] through their rat models, observed that the development of OPIDP may be mediated partly with an increase in oxidative stress.
CHRONIC TOXICITY
Neurodegeneration may occur from exposure to organophosphates at small subclinical does and may be referred to as organophosphate-induced chronic neurotoxicity or OPICN.[46] Another chronic toxicity develops from exposure to large doses of organophosphates and usually proceeds acute toxicity, this is named chronic organophosphate-induced neuropsychiatric disorder or copind.[48]
Anxiety, apathy, confusion, disorientation, impaired memory and concentration, irritability, speech difficulties, delayed reaction times, dizziness, and insomnia are some of the signs and symptoms. Others include decreased verbal attention, decreased academic skills, short-term memory deficits, increased social isolation, fatigue, impaired vigilance as well as slow reaction time.[46] There have also been studies to show that there could be a correlation between subclinical doses and diabetes among Indian farmers.[49]
Improvement is usually slow due to the fact that central and peripheral nervous systems have a greater damage.[46]
CONCLUSION
Organophosphate chemicals despite being used as pesticides and insecticides pose a huge risk to human health. There is the need for general public sensitization on the dangers of exposure to organophosphate pesticides be it for agricultural or household use. The use of protective equipment by pesticide applicators as well as other risk populations should be encouraged. Individuals who are frequently exposed to low doses of organophosphates should periodically evaluate their health status to enable them to seek professional help and counseling.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Kwong TC. Organophosphate pesticides: Biochemistry and clinical toxicology Ther Drug Monit. 2002;24:144–9
2. Bradman A, Castorina R, Barr DB, Chevrier J, Harnly ME, Eisen EA, et al Determinants of organophosphorus pesticide urinary metabolite levels in young children living in an agricultural community Int J Environ Res Public Health. 2011;8:1061–83
3. Rusyniak DE, Nañagas KA. Organophosphate poisoning Semin Neurol. 2004;24:197–204
4. Husain K. Delayed neurotoxicity of organophosphorus compounds J Environ Immunol Toxicol. 2013;1:14–21
5. Gupta RC. Toxicology of Organophosphate and Carbamate Compounds 20061st London Elsevier Academic Press:5–24
6. Davies R, Ahmed G, Freer T. Chronic exposure to organophosphates: Background and clinical picture Adv Psychiat Treat. 2000;6:187–92
7. Newmark J. Nerve agents: Pathophysiology and treatment of poisoning Semin Neurol. 2004;24:185–96
8. Szinicz L. History of chemical and biological warfare agents Toxicology. 2005;214:167–81
9. Delfino RT, Ribeiro TS, Figueroa-Villar JD. Organophosphorus compounds as chemical warfare agents: A review J Braz Chem Soc. 2009;20:407–28
10. Rosas LG, Eskenazi B. Pesticides and child neurodevelopment Curr Opin Pediatr. 2008;20:191–7
11. Rastogi SK, Satyanarayan PV, Ravishankar D, Tripathi S. A study on oxidative stress and antioxidant status of agricultural workers exposed to organophosphorus insecticides during spraying Indian J Occup Environ Med. 2009;13:131–4
12. Heckel DG. Ecology. Insecticide resistance after Silent spring Science. 2012;337:1612–4
13. Wilson G. DDT and the American century: Global health, environmental politics, and the pesticide that changed the world by David Kinkela (review) J World Hist. 2013;24:250–3
14. Ross SM, McManus IC, Harrison V, Mason O. Neurobehavioural problems following low-level exposure to organophosphate pesticides: A systematic and meta-analytic review Crit Rev Toxicol. 2013;43:21–44
15. Akan JC, Jafiya L, Mohammed Z, Abdulrahman FI. Organophosphorus pesticide residues in vegetables and soil samples from alau dam and gongulong agricultural areas, Borno State, Nigeria Int J Environ Monit Anal. 2013;1:58–64
16. Van Dyk JS, Pletschke B. Review on the use of enzymes for the detection of organochlorine, organophosphate and carbamate pesticides in the environment Chemosphere. 2011;82:291–307
17. Schmidt KG, Horowitz Y, Buckman G, Segev E, Levinger E, Geyer O. Lowering of IOP by echothiophate iodide in pseudophakic eyes with glaucoma Curr Eye Res. 2010;35:698–702
18. Ruark CD, Hack CE, Robinson PJ, Anderson PE, Gearhart JM. Quantitative structure-activity relationships for organophosphates binding to acetylcholinesterase Arch Toxicol. 2013;87:281–9
19. Guimarães AP, França TC, Ramalho TC, Rennó MN, da Cunha EF, Matos KS, et al Docking studies and effects of syn-anti isomery of oximes derived from pyridine imidazol bicycled systems as potential human acetylcholinesterase reactivators J Appl Biomed. 2011;9:163–71
20. Jokanović M, Stojiljković MP. Current understanding of the application of pyridinium oximes as cholinesterase reactivators in treatment of organophosphate poisoning Eur J Pharmacol. 2006;553:10–7
21. Buckley NA, Eddleston M, Li Y, Bevan M, Robertson J. Oximes for acute organophosphate pesticide poisoning Cochrane Syst Rev. 2011;2011:1–44
22. Kazemi M, Tahmasbi AM, Valizadeh R, Naserian AA, Soni A. Organophosphate pesticides: A general review Agric Sci Res J. 2012;29:512–22
23. Rohlman DS, Anger WK, Lein PJ. Correlating neurobehavioural performance with biomarkers of organophosphorous pesticide exposure Neurotoxicology. 2011;32:268–76
24. Sadasivam S, Krishna SK, Ponnusamy K, Nagarajan GS, Kang TW, Venkatesalu SC. Equilibrium and thermodynamic studies on the adsorption of an organophosphorous pesticide onto “waste” jute fiber carbon J Chem Eng Data. 2010;55:5658–62
25. Hsu CF, Tsai MJ, Chen KC, Wu RC, Hu SC. Can mortality from agricultural pesticide poisoning be predicted in the emergency department? Findings from a hospital-based study in eastern Taiwan Tzu Chi Med J. 2013;25:32–8
26. Chowdhary S, Bhattacharyya R, Banerjee D. Acute organophosphorus poisoning Clin Chim Acta. 2014;431:66–76
27. Shetye JV, Surkar SM, Karnik ND, Mehta AA. Delayed onset neuropathy along with recurrent laryngeal nerve palsy due to organophosphate poisoning and the role of physiotherapy rehabilitation Indian J Crit Care Med. 2014;18:102–4
28. Jokanović M, Kosanović M. Neurotoxic effects in patients poisoned with organophosphorus pesticides Environ Toxicol Pharmacol. 2010;29:195–201
29. Peter JV, Thomas L, Graham PL, Moran JL, Abhilash KP, Jasmine S, et al Performance of clinical scoring systems in acute organophosphate poisoning Clin Toxicol. 2013;51:850–4
30. Balali-Mood M, Saber H. Recent advances in the treatment of organophosphorous poisonings Iran J Med Sci. 2012;37:74–91
31. Jokanović M, Škrbić R. Neurotoxic disorders and medical management of patients poisoned with organophosphorus pesticides Scr Med (Banja Luka). 2012;43:91–8
32. Bird SB, Gaspari RJ, Dickson EW. Early death due to severe organophosphate poisoning is a centrally mediated process Acad Emerg Med. 2003;10:295–8
33. Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning Lancet. 2008;371:597–607
34. Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisoning Lancet. 2008;371:597–607
35. Senanayake N, Karalliedde L. Neurotoxic effects of organophosphorus insecticides. An intermediate syndrome N Engl J Med. 1987;316:761–3
36. Abdollahi M, Karami-Mohajeri S. A comprehensive review on experimental and clinical findings in intermediate syndrome caused by organophosphate poisoning Toxicol Appl Pharmacol. 2012;258:309–14
37. Das S, Chatterjee K, Sarkar N, Aich B, Dolui S. Cholinergic crisis, intermediate syndrome and delayed polyneuropathy following malathion poisoning J Pediatr Intensive Care. 2013;2:137–41
38. Jokanović M, Kosanović M, Brkić D, Vukomanović P. Organophosphate induced delayed polyneuropathy in man: An overview Clin Neurol Neurosurg. 2011;113:7–10
39. Vucinić S, Antonijević B, Ilić NV, Ilić TV. Oxime and atropine failure to prevent intermediate syndrome development in acute organophosphate poisoning Vojnosanit Pregl. 2013;70:420–3
40. Indira M, Andrews MA, Rakesh TP. Incidence, predictors, and outcome of intermediate syndrome in cholinergic insecticide poisoning: A prospective observational cohort study Clin Toxicol (Phila). 2013;51:838–45
41. Emerick GL, DeOliveira GH, dos Santos AC, Ehrich M. Mechanisms for consideration for intervention in the development of organophosphorus-induced delayed neuropathy Chem Biol Interact. 2012;199:177–84
42. Lotti M, Moretto A. Organophosphate-induced delayed polyneuropathy Toxicol Rev. 2005;24:37–49
43. Kavitha K, Kumar BK, Reddy AG. Alleviation of chlorpyrifos-induced delayed neurotoxicity with Vitamin E and phenytoin in hens Int J Pharmacol Biol Sci. 2013;4:207–20
44. Vasconcellos LF, Leite AC, Nascimento OJ. Organophosphate-induced delayed neuropathy: Case report Arq Neuropsiquiatr. 2002;60:1003–7
45. Glynn P. A mechanism for organophosphate-induced delayed neuropathy Toxicol Lett. 2006;162:94–7
46. Abou-Donia MB. Organophosphorus ester-induced chronic neurotoxicity Arch Environ Health. 2003;58:484–97
47. Masoud A, Sandhir R. Increased oxidative stress is associated with the development of organophosphate-induced delayed neuropathy Hum Exp Toxicol. 2012;31:1214–27
48. Jamal GA, Hansen S, Julu PO. Low level exposures to organophosphorus esters may cause neurotoxicity Toxicology. 2002:181–182–33:23–182–33
49. Velmurugan G, Ramprasath T, Swaminathan K, Mithieux G, Rajendhran J, Dhivakar M, et al Gut microbial degradation of organophosphate insecticides-induces glucose intolerance via gluconeogenesis Genome Biol. 2017;18:8.
