Organophosphorous

Priti KumariORGANOPHOSPHOROUS POISONINGCauses and Consequences

What are Organophosphorous Compounds ?Organophosphorus (OP) compounds are usually esters, amides or thiol derivatives of phosphonic acid and form a large family (> 50 000 compounds) of chemical agents with biological properties that have important, and sometimes unique, applications for the benefit of mankind.A large group of chemicals used for protecting crops, livestock, human health and as warfare agents.On the basis of structural characteristics they are divided into at least 13 types : phosphates, phosphonates, phosphinates, phosphorothioates (S=), phosphonothioates (S=), phosphorothioates (S substituted), phosphonothioates (S substituted), phosphorodithioates, phosphorotrithioates, phosphoramidothioates (Gupta, 2006).They are also been used as plasticizers, stabilizers in lubricating and hydraulic oils, flame retardants, and gasoline additives.The first OPs were synthesised in the 19th century, used widely in the 1930s. The German chemist Gerhard Schrader synthesised many commercial OPs of which parathion (Figure 2) is still used as a common pesticide. At the beginning of the Second World War the development of OP substances switched to highly toxic compounds employed as nerve warfare agents, e.g. sarin, soman and tabun (Figure 3).

Fig : 1 Basic Structure of OPs InsecticideWhere X is the so-called leaving group, that is displaced when the OP phosphorylates acetylcholinesterase (AChE), and is the most sensitive to hydrolysis;R1 andR2 are most commonly alkoxy groups (i.e., OCH3 or OC2H5), though other chemical substitutes are also possible; either an oxygen or a sulfur (in this case the compound should be defined as a phosphorothioate) are also attached to thephosphorus with a double bond.

SOURCE : Toxicology- The Basic Science of Poison

Fig. 2. Two examples of OP pesticides: (a) methyl-parathion with a bonded S atom; (b) methyl-paraoxon with a bonded O atom.Fig. 3. The structure of toxic OP warfare agents: (a) tabun, (b) soman, (c) sarin

OPs as Warfare AgentsOne of the greatest threats in modern world is the possibility of use of chemical weapons by regular forces or by terrorist groups. Among these weapons, the so-called neurotoxic agents, commonly known as nerve agents, constitute the greatest concern, due to their highly deleterious effects on humans.

Certain OPs Nerve Gases : soman, sarin, tabun, VX1936 : The German chemist Gerhard Schrader synthesizes the neurotoxic agent tabun.1937 : Schrader and coworkers synthesize the neurotoxic agent sarin by IG Farben chemical company in Nazi Germany.A single droplet of Sarin or VX, if inhaled or in contact with the skin, can be absorbed into the bloodstream and paralyze the nervous system, leading to respiratory failure and immediate death..1950s : VX is synthesized by the British and weaponized by the Americans.1980-1988 : First time used in Iran-Iraq War. Iraq used Tabun and Sarin against Iranian.1994 :Terrorist attack with sarin in Matsumoto, Japan, executed by the Aum Shinrikyo sect, results in 7 deaths and more than 300 injured1995 : Terrorists released sarin in trains on three different Tokyo subway lines; 5500 intoxicated; 11 mortalities.VX is now banned by the Chemical Weapons Convention of 1993.

SOURCE : Delfino et al.

OPs as PesticidesMost widely used pesticides for insects control.First OP insecticide : Tetraethylpyrophosphate (TEPP), approved in Germany in 1994; marketed as substitute for Nicotine to control Aphids.Because of its high mammalian toxicity and rapid hydrolysis in water, TEPP was replaced by other OP insecticides.Chlorpyrifos : one of the largest selling insecticides in the world; both agricultural and urban uses.Parathion was another widely used insecticide due to its stability in aqueous solutions and its broad range of insecticidal activity. However, its high mammalian toxicity through all routes of exposure led to the development of less hazardous compounds.Malathion [diethyl (dimethoxythiophosphorylthio)succinate], in particular, has low mammalian toxicity because mammals possess certain enzymes, the carboxylesterases, that readily hydrolyze the carboxyester link, detoxifying the compound.

SOURCE : A Textbook of Modern Toxicology by Ernest Hodgson

Chlorpyrifos : banned in most of the countries still used in IndiaMalathion : still used in IndiaDiazinon : banned for use in agriculture except for household use. (S.O.45 (E) dated 08th Jan, 2008)Fenitrothion : banned in Agriculture except for locust control in scheduled desert area and public health. (S.O.706 (E) dated 03rdMay, 2007)Fenthion : banned in Agriculture except for locust control, household and public health. (S.O.46 (E) dated 08th Jan, 2008) Parathion : Methyl Parathion 50 % EC and 2% DP formulations are banned for use on fruits and vegetables. (S.O.680 (E) dated 17thJuly, 2001)

SOURCE : cibrc.nic.in/ibr2012.doc

, 16 JULY, 2013 : Masrakh Dharmashati Gadaman Prathmik Vidyalaya, Masrakh, Chapra, Bihar Head Mistress : Meena Devi Accidental Pesticide Poisoning : During Mid day meal 23 children died by eating pesticide contaminated mid day meal. CARELESSNESS : 1. Used Cooking oil was stored in container formerly used to store insecticides. 2. The food given to children should be tasted first by HM, which was not happened. Pesticide found : MONOCROTOPHOS (OP)SOURCE : www.ibnlive.com

SOURCE : www.washingtontimes.comSYRIAN CIVIL WAR, 19 March 2013 In Khan-al-Assal, Aleppo, SyriaWeapon : Rocket fillled with Sarin 26 fatalities including 16 gov. Soldeirs and 10 civilians. More than 86 injured

GHOUTA ATTACK, 21 August, 2013 1729 fatalities

POISONING and TOXICITYPoison : Poison is a substance ( solid/ liquid or gaseous ), which if introduced in the living body, or brought into contact with any part there of, will produce ill health or death, by its constitutional or local effects or both.Poisoning : The development of dose related adverse effects following exposure to chemicals, drugs or other xenobiotics.

SOURCE : The Essentials of Forensic Medicine and Toxicology : Dr. K. Reddy

Toxicity : The ability of a chemical to do systemic damage to an organism.Acute Toxicity : The ability of a chemical to harm an organism as a result of a relatively short one-time exposure. Chronic Toxicity : The ability of a chemical to cause harm to an organism as a result of repeated exposures for long periods of time perhaps even a lifetime.

SOURCE : www.analysisonline.org

STATUSAssociated with serious human toxicity, accounting for more than 80% of pesticide-related hospitalizations.Most cases occur in the developing world as a result of occupational or deliberate exposure to organophosphorus pesticides. Although data are sparse, organophosphorus pesticides seem to be the most important cause of death from deliberate self poisoning worldwide, causing about 200,000 deaths each year.The potential adverse impact on human health from exposure to pesticides is likely to be higher in countries like India due to easy availability of highly hazardous products, and low risk awareness, especially among children and women.Overexposure to pesticides can occur before spraying because of easy access for children, lack of adequate labelling and during mixing during spraying and after spraying operations. Spray operators and bystanders can be affected.Acute organophosphate (OP) poisoning is a significant cause of morbidity and mortality in developing countries including India. According to WHO, one million serious accidental and two million suicidal poisonings due to insecticides occur worldwide, every year, of which 200,000 die and most of these deaths occur in developing countries

The toxicity of OPs depends on their chemical structure, metabolism in target organism, concentration (i.e. dose), mode of application, degree of decomposition, mode of entering organisms, etc. The best described OP toxic effects are the neurological symptoms following acute poisoning as a consequence of the primary target (AcHE).

MECHANISM OF TOXICITY

CAUSES and CONSEQUENCESAcute organophosphorus poisoning occurs after dermal, respiratory, or oral exposure to either low volatility pesticides (e.g., chlorpyrifos, dimethoate) or high volatility nerve agents (e.g., sarin, tabun).Acetylcholinesterase inhibition by organophosphorus pesticides or organophosphate nerve agents can cause acute parasympathetic system dysfunction, muscle weakness, seizures, coma, and respiratory failure.Residues linger on fruits and vegetables.Absorption : The degree of absorption depends on the contact time with the skin, the lipophilicity of the agent involved and the presence of solvents. The rate of absorption also varies with the skin region affected. For example, parathion is absorbed more readily through scrotal skin, axillae and skin of the head and neck than it is through the skin of the hands and arms.Following absorption, OP compounds accumulate rapidly in fat, liver, kidneys and salivary glands.

Neurotoxicity of OPsOrganophosphate compounds avidly bind to cholinesterase molecules and share a similar chemical structure.In human beings, the two principal cholinesterases are RBC, or true cholinesterase (acetylcholinesterase), and serum cholinesterase (pseudocholinesterase).Normally the cholinesterases rapidly hydrolyze the neurotransmitter acetylcholine into inactive fragments of choline and acetic acid after the completion of neurochemical transmission.The entire process takes about 150 microsecondsThe neurotransmitter acetylcholine is present in the terminal endings of all postganglionic parasympathetic nerves, at myoneural junctions, and at both parasympathetic and sympathetic ganglia.The major toxicity of organophosphate compounds is the covalent binding of phosphate radicals to the active sites of the cholinesterases, transforming them into enzymatically inert proteins.Organophosphates thus act as irreversible cholinesterase inhibitors because the organophosphate-cholinesterase bond is not spontaneously reversible without pharmacological intervention.The inhibition of cholinesterase activity leads to the accumulation of acetylcholine at synapses, causing overstimulation and subsequent disruption of transmission in both the central and peripheral nervous systems.

Fig.4 : Neuromuscular JunctionFig.5 : ACh-ase activity and OP as inhibitor

Genotoxicity and Carcinogenecity of OPsChronic occupational exposure to OPs has been linked to increased risk for cancer development such as non-Hodgkin lymphoma (Waddell et al., 2001) and some types of leukaemia.Experimental in vitro and in vivo studies have shown that several OPs exert genotoxic activity and there are also reports showing that OPs can induce neoplastic transformation of cells (Cabello et al., 2001). OPs have been report : to induce chromosomal aberrations and sister chromatid exchange.

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Immunotoxicity of OPsDirect immunotoxic effects of OPs can be due to:1. inhibition of serine hydrolases (complement system) or esterases (lymphocyte and monocyte membranes) in the immune system;2. oxidative damage of immune system organs;3. changes in signal transduction pathways that control proliferation and immune cell differentiation.Indirect immunotoxicity of OPs is expressed as changes in the nervous system or chronic effects of altered metabolism on the immune system.

SOURCE : Organophosphorous Pesticides : Elersek Tina

What is immune system and its toxicity ?

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MEASURES DEALING WITH OPs POISONING

Assessment of Severity of OPC Poisoning

Normal Serum ACh-ase/ RBC Cholinesterase level : 8.0-20.0/lMILDMODERATESEVERE1. Fatigue, Headache1. Miosis1. Fasciculations (Generalised)2. Numbness Nausea & Vomiting2. General weakness2. Marked miosis (Absent pupillaryreaction)3. Diaphoresis, Salivation3. Dysarthria3. Flaccid Paralysis / Pulmonary crepitation4. Abdominal pain, Diarrhoea4. Fasciculations With symptoms of mild poisoning4. Respiratory distress5. Pt. Able to Ambulate5. Pt. Unable to Ambulate5. Cyanosis6. Pt. UnconsciousSerum ACh-enzyme Result : 1.6-4.0 /lSerum ACh-enzymeResult : 0.8-2.0/l Serum ACh-enzymeResult : 100. Atropine crosses the blood brain barrier and counters the effect of excess acetylcholine on the extrapyramidal system. PRALIDOXIMEOximes used as rejuvenators. The beneficial effect of oximes is exerted through the reactivation of enzyme cholinesterase by cleavage of the phosphorylated site and by a direct detoxifying effect on the unbounded organophosphorous compound. Additionally, oximes have an anticholinergic effect when used in normal doses. The recommended dose is 1 gm every 8 hours by intravenous injection.LOADING DOSE: IV 0.5-2 mg over 5-10 min until atropinization achieved

MAINTENANCE DOSE:(8 mg mix in 100 mL normal saline) at a rate of 0.02-0.08 mg/kg/hr PAM2 effective within 24 hours of exposure 1-2 g IV in 100 mL normal saline within 30min. repeat if muscle weakness did not relieve in 1 hour

Clearance of chest of secretions and maintenance of BP has been given more importance in the target point than size of pupiland heart rate.22

MEDICAL CARE

Airway control and adequate oxygenation are paramount in organophosphate (OP) poisonings. Intubation may be necessary in cases of respiratory distress due to laryngospasm, bronchospasm, bronchorrhea, or seizures. Immediate aggressive use of atropine may eliminate the need for intubation. Succinylcholine should be avoided because it is degraded by plasma cholinesterase and may result in prolonged paralysis. Continuous cardiac monitoring and pulse oximetry should be established; an ECG should be performed. The use of intravenous magnesium sulfate has been reported as beneficial for organophosphate toxicity. Remove all clothing and gently cleanse patients suspected of organophosphate exposure with soap and water because organophosphates are hydrolyzed readily in aqueous solutions with a high pH. Consider clothing as hazardous waste and discard accordingly. Use personal protective equipment, such as neoprene gloves and gowns, when decontaminating patients because hydrocarbons can penetrate nonpolar substances such as latex and vinyl. Use charcoal cartridge masks for respiratory protection when decontaminating patients who are significantly contaminated. Irrigate the eyes of patients who have had ocular exposure using isotonic sodium chloride solution or lactated Ringer's solution. Morgan lenses can be used for eye irrigation.Guided by : Col. H.S.Mishra Medical Officer, ECHS Armed Medical Corp.

Laryngospasm : Branchospasm : abnormal contraction of smooth muscles.

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Challengs In Country like IndiaInadequate Forensic laboratories in Government hospitals.Inadequate Poison Information Centres.Inadequate knowledge in utilizing the pesticides.Lack of health professionals in toxicological studies.Lack of availability of newer antidotes.Easy availability of OP compounds (especially pesticides) in the market.Indeterminate quantitative estimation in patients.Elevation of respiratory failure.Raised diaphragmatic paralysis.High exposure/consumption of pesticides develops acute hemorrhagic pancreatitis.Utilization of pesticides increases health hazard in individuals leading to decrease in GDP.

All these challenges we can make full stop, if we ban OP compounds in commercial market.

Instructions in local language

Diamond indicating hazardCommon household InsecticideMonocrotophosPesticides seller, Khandera Market, Vadodara

SUGGESTIONSAvoidance of contact with chemicals like pesticides. You should take the usual precautions like making sure theres adequate ventilation when using pesticides indoors.Washing all fresh fruit and vegetables before eating.Keep pesticides away from children.No working situation is safe, so precautions to avoid exposure should be taken.Try to use less pesticides : it saves money and reduces health risks.Keep always the pesticides in original container.It is always important to read the product label carefully.The label should be in local language- understandable to users.See a doctor if you do not feel well. Tell him that you work with pesticides.In case of First Aid : remove the patient to an uncontaminated and ventilated area.

CONCLUSIONOrganophosphates are found in pesticides and nerve gas. Due to their particularly sinister properties, many countries have banned the use of organophosphates in agriculture, however, this does not mean that there arent older organophosphates around in peoples sheds, homes, or garages. Furthermore, with the increasing fear of terrorist attacks, organophosphate based nerve gases, although unlikely, are always a possibility.

Organophosphates poisonings are becoming less common for paramedics, but hold a very high level of mortality and are dangerous for all persons involved. Because of this, paramedics must thoroughly understand the pathophysiology and signs and symptoms of organophosphate poisoning.

Education amongst the farmers of organophosphorus compounds regarding its proper manner of use and stringent laws in relation to its use as insecticides and pesticides in the burning need of the time to save the most commonly affected group by these toxic compounds.

In future, the ministry of agriculture of developing countries especially India, should concentrate on the optimization and monitoring of usage of OP compounds as pesticides and furthermore encouraging the farmers to use natural pesticides rather than chemical pesticides.

REFERENCEShttp://www.neurologyindia.comhttp://www.emergencymedicalparamedic.com/organophosphate-poisoning/http://www.bvsde.paho.org/bvstox/fulltext/Poisoningrev.pdfhttp://www.analysisonline.org/site/aoarticle_display.asp?sec_id=140002434&issue_id=5&news_id=140001678&pg=5http://www.toxipedia.org/display/dose/Pesticideshttp://www.dementiaguide.com/aboutdementia/treatments/cholinesterase_inhibitorshttp://www.dw.de/after-syria-why-the-chemical-weapon-sarin-is-an-invisible-and-indiscriminate-killer/a-17124208http://emedicine.medscape.com/article/167726-medicationhttp://www.chemicalbodyburden.org/cs_organophos.htmhttp://www.atsdr.cdc.gov/csem/cholinesterase/docs/cholinesterase.pdfhttp://www.epa.gov/pesticides/safety/healthcarehttp://www.intechopen.com http://www.washington.comhttp://www.ibnlive.com

REFERENCESBalali-Mood M., Abdollahi M.(eds.), Basic and Clinical Toxicology of Organophosphorus Compounds; Pg-25, Springer-Verlag London 2014Casarette & Doulls; Toxicology- The Basic Science of Poisons, 7th Edition-2008Delfino R.T., Ribeiro T.S. and Figueroa-VillarJ.D.; Organophosphorus Compounds as Chemical Warfare Agents: a Review; J. Braz. Chem. Soc., Vol. 20, No. 3, 2009Eddleston M., Buckley N.A., Eyer P., Dawson A.H; Management of Acute Organophosphorous Pesticide Poisoning; Lancet 2008; 371: 597607Hodgson E. A Textbook of Modern Toxicology-3rd edition; 2004- Ch: 5; Pg: 58Jayasinghe SS, Pathirana KD, Buckley NA (2012) Effects of Acute Organophosphorus Poisoning on Function of Peripheral Nerves: A Cohort Study. PLoSONE 7(11): e49405. doi:10.1371/journal.pone.0049405Katz Kenneth D, Brooks Daniel E. Toxicity, Organophosphate. Last updated May 13 2009 http/www.emedicine.medscape. comKumar S.V., Fareedullah Md., Sudhakar y., Venkateswarlu B. and Kumar A.E; Current review on organophosphorus poisoning ; Archives of Applied Science Research, 2010, 2 (4): 199-215

REFERENCESMileson B.E., Chambers J.E., Chen W.L.et.al, Common Mechanism of Toxicity: A Case Study of Organophosphorus Pesticides; Toxicological Sciences 41, Pg8-20, 1998Patel D.J.and Tekade P.R.; Profile of Organophosphorus Poisoning at Maharani Hospital, Jagdalpur, Chhattisgarh: A Three Years Study; J Indian Acad Forensic Med. April-June 2011, Vol. 33, No. 2Palaniappen V.; Current Concepts in the Management of Organophosphorus Compound Poisoning Reddy K.; The Essentials of Forensic Medicine and Toxicology., Section II Toxicology; 25th editionWaddell, B.L.; Zahm, S.H.; Baris, D.; Weisenburger, D.D.; Holmes, F.; Burmeister, L.F.; Cantor, K.P. & Blair, A. (2001) Agricultural use of organophosphate pesticides and the risk of non-Hodgkin's lymphoma among male farmers (United States). Cancer Causes and Control 12 (6): 509-517 WHO, 1985 : Safe Use of Pesticides, Technical Report Series, 720, World Health Organization.

PREVENTION IS BETTER THAN CURETHANK YOU