Priti Kumari

ORGANOPHOSPHOROUS POISONING

Causes 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 Insecticide

Where 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 the

phosphorus 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 Agents

One 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, VX

1936 : 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..

1950’s : 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 injured

1995 : 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 Pesticides

Most 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 India

Malathion : still used in India

Diazinon : 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

सावधानी हटी, द ू्र्घटना र्टी

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.com

SYRIAN CIVIL WAR, 19 March 2013

• In Khan-al-Assal, Aleppo, Syria

•Weapon : 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 TOXICITY

Poison : “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

STATUS

Associated 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 CONSEQUENCES

Acute 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 OPs

Organophosphate 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 microseconds

The 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 OPs

Chronic 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.

Immunotoxicity of OPs

Direct 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

MEASURES DEALING WITH OPs

POISONING

Assessment of Severity of OPC Poisoning

Normal Serum ACh-ase/ RBC Cholinesterase level : 8.0-20.0µ/l

MILD MODERATE SEVERE

1. Fatigue, Headache 1. Miosis 1. Fasciculations

(Generalised)

2. Numbness Nausea &

Vomiting

2. General weakness 2. Marked miosis (Absent

pupillary

reaction)

3. Diaphoresis, Salivation 3. Dysarthria 3. Flaccid Paralysis /

Pulmonary crepitation

4. Abdominal pain, Diarrhoea 4. Fasciculations With

symptoms of mild poisoning

4. Respiratory distress

5. Pt. Able to Ambulate 5. Pt. Unable to Ambulate 5. Cyanosis

6. Pt. Unconscious

Serum ACh-enzyme

Result : 1.6-4.0 µ/l

Serum ACh-enzyme

Result : 0.8-2.0µ/l

Serum ACh-enzyme

Result : <0.8µ/l

TREATMENTATROPINE

• used as an antidote to counter the muscarinic effects of

acetylcholine; only life saving antidote.

• Atropinisation, once achieved, should be maintained for 3-5 days,

depending upon the compound involved. When muscular

paralysis supervenes, mechanical ventilation is required.

• Atropinisation is evidenced by pupillary dilation, drying up of

secretions and pulse rate > 100. Atropine crosses the blood brain

barrier and counters the effect of excess acetylcholine on the

extrapyramidal system.

PRALIDOXIME

• Oximes 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

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.

Challengs In Country like India

Inadequate 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

languageDiamond indicating

hazard

Common household

Insecticide

Monocrotophos

Pesticides seller,

Khandera Market,

Vadodara

SUGGESTIONS

Avoidance of contact with chemicals like pesticides.

You should take the usual precautions like making sure there’s 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.

CONCLUSION

Organophosphates are found in pesticides and nerve gas. Due to their particularly sinister properties, manycountries have banned the use of organophosphates in agriculture, however, this does not mean that there aren’tolder organophosphates around in peoples sheds, homes, or garages. Furthermore, with the increasing fear ofterrorist 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 mortalityand are dangerous for all persons involved. Because of this, paramedics must thoroughly understand thepathophysiology and signs and symptoms of organophosphate poisoning.

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

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

REFERENCES http://www.neurologyindia.com

http://www.emergencymedicalparamedic.com/organophosphate-poisoning/

http://www.bvsde.paho.org/bvstox/fulltext/Poisoningrev.pdf

http://www.analysisonline.org/site/aoarticle_display.asp?sec_id=140002434&issue_id=5&news_id=140001678&pg=5

http://www.toxipedia.org/display/dose/Pesticides

http://www.dementiaguide.com/aboutdementia/treatments/cholinesterase_inhibitors

http://www.dw.de/after-syria-why-the-chemical-weapon-sarin-is-an-invisible-and-indiscriminate-killer/a-17124208

http://emedicine.medscape.com/article/167726-medication

http://www.chemicalbodyburden.org/cs_organophos.htm

http://www.atsdr.cdc.gov/csem/cholinesterase/docs/cholinesterase.pdf

http://www.epa.gov/pesticides/safety/healthcare

http://www.intechopen.com

http://www.washington.com

http://www.ibnlive.com

REFERENCES Balali-Mood M., Abdollahi M.(eds.), Basic and Clinical Toxicology of Organophosphorus Compounds;

Pg-25, © Springer-Verlag London 2014

Casarette & Doull’s; Toxicology- The Basic Science of Poisons, 7th Edition-2008

Delfino 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, 2009

Eddleston M., Buckley N.A., Eyer P., Dawson A.H; Management of Acute Organophosphorous

Pesticide Poisoning; Lancet 2008; 371: 597–607

Hodgson E. A Textbook of Modern Toxicology-3rd edition; 2004- Ch: 5; Pg: 58

Jayasinghe 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.0049405

Katz Kenneth D, Brooks Daniel E. Toxicity, Organophosphate. Last updated May 13 2009

http/www.emedicine.medscape. com

Kumar 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

REFERENCES Mileson 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, 1998

Patel 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. 2

Palaniappen V.; Current Concepts in the Management of Organophosphorus Compound Poisoning

Reddy K.; The Essentials of Forensic Medicine and Toxicology., Section II Toxicology; 25th edition

Waddell, 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 CURE