Pesticide Poisoning Is A Major Health Problem Biology Essay

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Pesticide poisoning is a major health problem worldwide. According to WHO, annually one million accidental and two million suicidal poisoning cases are due to insecticides. Since third world countries account for approximately one-fourth of total consumption of insecticides, the situation is worse in these regions.1 Organophosphate compounds are frequently used as poisons due to their easy availability. Moreover, with use of OP compounds as chemical warfare agents (e.g. Sarin, Tabun); these compounds have gained much more attention rather than just being insecticides. In India, it is the most common poisoning and approximately 50% of cases are accounted by them.2 Most of the cases are with suicidal intent while poisoning due to accidental exposure include neglect of protective measures in agricultural and industrial workers (e.g. use of vinyl made gloves instead of rubber), contaminated food and water etc. Food borne exposures have resulted in epidemics such as "Ginger Jake paralysis" (delayed neuropathy) due to contamination of an alcoholic drink with triorthocresylphosphate (TOCP) 3 and with mild to moderate symptoms with use of insecticide aldicarb on watermelons.4 In a prospective study, OP compounds were the second most common used poisons, accounting for 13.9 % of cases.5 A decade later, in a study revealing trends of poisoning in Haryana, 355 cases were admitted in year with alleged history of poisoning with OP compounds in PGIMS, Rohtak and continued to be second most commonly used poisonous substance (29.17%).6

Organophosphate Compounds:

Organophosphate compounds are diverse group of chemicals comprising of esters, amides or thiol derivatives of phosphoric acid derivatives.7 They were first synthesized in 1850's with the modern products tracing back to development in Germany in 1930's.They are widely used as insecticides and fungicides and are commonly known among Indians as sprays. However, they are found to have clinical use in treatment of glaucoma, myasthenia gravis and Alzheimer's disease. The rapid degradation by hydrolysis on exposure to sunlight, air and subsequently acute toxicity make them favorites among pesticides. The various types of organophosphate compounds and the uses are given in Table I:

TableI: OP compounds and their uses



Malathion, Parathion, Diazinon, Fenthion, Dichlorovas, Chlorpyrifos


Soman, Sarin, Tabun, VX

Nerve gases

Tribufos, Merphos



Antihelminthic agents

Mechanism of action: Organophosphates inactivate the enzyme Acetylcholinesterase (AchE) by reacting at the esteratic site and forming a covalent phosphate linkage at the enzyme active site. AchE inhibition allows the Ach (Acetylcholine) to accumulate and remain active in synapse thus resulting in sustained depolarization of the postsynaptic neurons in central nervous system, muscarinic sites, nicotinic site in the sympathetic and parasympathetic ganglia, and nicotinic sites at neuromuscular junction. In general, effects of muscarinic sites are sustained, whereas nicotinic sites are stimulated and then depressed (hyperpolarisation block).8

The profound toxicity of these compounds is attributed to non reversible binding to enzyme Acetylcholinesterase (AchE). Enzyme regeneration depends upon de novo synthesis, hydrolysis of the serine - phosphate compound or oxime (described ahead) regeneration however over a period of 24-48 hours most of phosphyralated compounds become resistant to reactivation or go under aging (a process in which the bond between organophosphate and AchE become irreverisble with time due to separation of one of alkyl radicals from OPs) resulting in severe and irreverisible toxic effects.

Modes of poisoning: Organophosphate compounds can be absorbed through skin, conjunctiva by direct contact, GIT and oral mucosa by ingestion and respiratory route through inhalation. The patients become symptomatic depending upon the nature of compound, amount, route of exposure and rate of metabolic degradation. Onset of symptoms is as early as 3-4 hrs by inhalation/ oral route to 10-12 hrs through dermal route. They are distributed rapidly in all body tissues after absorption and the high lipid solubility of these compounds makes their access easy in CNS and fat tissues. Onset may be delayed for lipophilic compounds (e.g. fenthion, diclofenthion) 9 or compounds requiring conversion to more toxic metabolite (e.g. hepatic metabolism of parathion to paraoxon).10 The intermittent release of toxin from the fat tissues accounts for the deterioration of the stable patient.

Clinical features (Fig.1)

The clinical features are due to stimulation of muscarinic, nicotinic and central receptors and delayed neurotoxicity.

Muscarinic Features : The accumulation of Ach at postganglionic muscarinic receptors leads to increased parasympathetic activity of smooth muscle in lungs, GIT, heart, eyes, bladder, secretory glands and increased sympathetic discharge for sweat glands and the consequent manifestations can be easily remembered by pneumonic SLUDGE/BBB (Salivation, Lacrimation, Urination, Defecation, GI symptoms, Emesis, Bronchorrhea, Bronchospasm, Bradycardia) or DUMBELS (Diarrhea, Diaphoresis, Urination, Miosis, Bronchospasm, Bradycardia, Emesis, Lacrimation, Salivation). Miosis may be most sensitive marker amongst lacrimation, rhinorrhea and profuse sweating in moderate to severe poisoning whereas abdominal cramps, diarrhoea and vomiting are more common in severe poisoning.

Nicotinic Effects: Fasciculations, progressive weakness and hypotonia are due to excessive Ach at nicotinic muscle end plates causing persistent depolarization of skeletal muscle. Respiratory failure due to bronchial spasm, noncardiogenic pulmonary oedema and respiratory muscle paralysis is a common cause of death due to OP poisons. Cardiac toxicity comprises of phases including a brief period of intense sympathomimetic tone, a period of enhanced parasympathetic activity, and prolongation of QTc.8 Other cardiovascular effects include hypertension, tachycardia, reentrant arrhythmias and torsade de pointes etc.

CNS Effects: Organophosphate compounds cross blood brain barrier, they may cause seizures, choreoathetoid movements, ataxia, dysarthrias, tremors, absent or exaggerated reflexes, anxiety, agitation, emotional labilities, slurred speech etc.

Delayed Neurotoxicity: Altered conscious state after 4-5 days leading to deep coma, encephalopathy11, dystonia, cogwheel rigidity and parkinsonian features12,13 (basal ganglia impairment after recovery from acute toxicity) has also been reported.

The clinical manifestations seen with OP poisoning can be seen as in Fig.2.

Grading of organophosphate poisoning has been formulated according to severity on various clinical and biochemical parameters and is shown in table II.

Table II. Grading of Organophosphate Poisoning14

Organophosphate poisoning: Severity Grade




Walks and talks

Cannot walk




No pupillary reflex

Nausea, Vomiting

Muscle twitching, Fasciculations

Flaccid paralysis, Fasciculations

Abdominal pain

Anxiety, Restlessness

Increased bronchial secretion

Sweating, Salivation


Dyspnoea, crackles, wheeze



Respiratory failure


1.6-4 U/L ( AchE 20-50% of normal*)

0.8-2 U/L (AchE 10-20% of normal)

<0.8 U/L (AchE < 10% of normal)

*Normal value of serum AchE is 8-20 U/L.

Diagnosis of organophosphate poisoning

History of exposure to organophosphate compound in the presence of signs and symptoms usually clinches the diagnosis which is confirmed by low AchE levels. The compounds inhibit both plasma cholinesterase (also called butyrylcholineesterase or pseudocholineesterase) and RBC cholinesterase. RBC AchE levels are more specific than plasma AchE levels since RBC AchE has similar structure to synapyic AchE.15 AchE levels < 10% of normal indicate severe toxicity whereas levels 20-50% and 10-20% account for mild and moderate toxicity respectively.

Several OP compounds are metabolized to p-nitrophenol which can be easily detected in urine.16 Serum levels of OP compounds, though of little relevance in patient management yet help in determining the residual OP residue in patients with prolonged signs of toxicity. Supplemental studies include serum electrolyte, blood urea nitrogen, creatinine, glucose, calcium, magnesium, electrocardiography and chest radiography.

Differential diagnosis includes toxicity due to carbamates, nicotine, carbachol, bethanechol, pilocarpine, mushrooms and cholinergic crisis like in myasthenia gravis and Eaton-Lambert's syndrome. Signs and symptoms of carbamate poisoning closely resembles that of OP poisoning, however the oximes are not recommended owing to early hydrolysis of carbamylated enzyme, thus easy reverisibility and non ageing of the carbamylated enzymes (c.f. Phosphyralated enzymes- may undergo ageing by losing one of the alkyl group, thus becoming resistant to hydrolysis).

The schematic representation pertaining to diagnosis is given in Fig.3


Organophosphate poisoning is a medical emergency. Life can be saved by early diagnosis and effective treatment. Patients should be admitted and observed carefully. The persons involved in managing these patients should preferably wear masks, aprons, and rubber gloves to avoid secondary contamination. Treatment includes decontamination, general supportive measures and specific treatment.

Decontamination and methods to retard the absorption of poison: In case of contact with poison, the removal of clothes and thorough washing of body with soap and water should be done (organophosphate compounds get hydrolysed in aqueous solution at high pH). Skin folds, hair and nails should be thoroughly cleaned. Ocular decontamination should be done with water/ normal saline. Gastric decontamination in form of gastric lavage should be carried out with KMnO4. The slurry of activated charcoal can be left in stomach to absorb the residual poison. Gastric lavage should be repeated every 3-4 hrs to remove any residual poison secreted in stomach due to release from fat stores.17 Forced emesis and syrup ipecac have no role.18

General supportive measures: it includes the basic principles of resuscitation i.e.

A- Airway should be secured to prevent aspiration by oropharyngeal suction, endotracheal intubation.

B- Breathing by ambubag or mechanical ventilation.

C- Circulation- hydrate the patient by securing wide bore IV lines.

D- Detoxification by antidotes

Specific treatment:

Anticholinergic drugs: These agents are the mainstay of treatment. These act as competitive antagonists of Ach at muscarinic receptors leading to reversal of muscarinic effects of organophosphate compounds both in CNS and periphery.

Atropine: It is life saving antidote leading to reversal of muscarinic effects but has no effect on muscle weakness/paralysis and regeneration of AchE. Early administration of drug in appropriate dose is an essential part of management. Atropine has been shown to have secondary role in controlling seizures and CNS manifestations in addition to primary role in clearing of secretions and bronchospasm.19

Atropine regimens:

Intermittent regimen - Atropine has to be started at 1-3 mg iv bolus dose with increment of the dose to be doubled every 5 minutes till the target end points of atropine therapy ( pupils no longer pinpointed, clear chest on auscultation with no wheeze, dry axilla, systolic blood pressure > 80 mm Hg and heart rate > 80 bpm ) are achieved.20 However, tachycardia is not a good indicators of atropinisation since the condition can occur due to nicotinic symptoms, hypoxia or due to sympathetic over reactivity. Similarly, pupil dilatation may result due to hypoxic damage to the brain rather than being a sign of atropinisation.

Continuous infusion therapy - Continuous infusion of atropine at the rate of 0.02-0.08 mg/kg/hr following bolus injection has been also investigated and proven to be useful as it requires less observation, produces less fluctuation in plasma atropine concentration which makes weaning easier.21 In addition, atropine infusion at a rate of 10-20% of atropine required for atropinization every hour by I/V infusion has also been found to be useful in managing the patients.22 If very large doses (more than 30 mg) were initially required, then less can be used. It is rare that an infusion rate greater than 3-5 mg/ hour is necessary however, larger doses may be required if oximes are not available.20

Atropine tapering - The atropine dosages has to be maintained by increasing the dose interval gradually from 5- 15 min to a period of 2-3 hrs over a period of 3-5 days and subsequent withdrawal of atropine on 5th-7th day.

The various atropine regimens can be described by simple algorithm as in fig.4

Atropine toxicity: It includes confusion, agitation, hyperthermia, ileus and tachycardia.23 The drug should be stopped immediately till the signs of over atropinisation remain. The drug can be restarted at rate of 70-80% of previous dose when the features of toxicity settle down. The patient should then be seen frequently to ensure that the new infusion rate has reduced the signs of atropine toxicity without permitting the reappearance of cholinergic signs.

Glycopyrrolate: It is an alternative to atropine. It does not cross the blood brain barrier, hence the CNS symptoms like coma and confusion do not respond. It is used as an adjunct to atropine in case of copious secretions, in atropine toxicity or if atropine is not available. It is given as 0.05mg/kg body weight and is titrated till the desired effect of dry mucous membranes is achieved. The additional advantage of glycopyrrolate studied is the less chances of respiratory infections.24

Cholinesterase reactivators: These agents, commonly known as oximes (pralidoxime, obidoxime) get attached to free anionic site of enzyme AchE. The oximes then react with phosphorus atom of organophosphate attached at the esteratic site of the enzyme, thus forming oxime phosphate which gets easily diffused leaving AchE intact. In addition, they slow the ageing of phosphorylated enzyme complex and also convert the organophosphate compound to a harmless one.25 Oximes do not cross the blood brain barrier; hence the action is limited to the skeletal muscle and autonomic sites (reverses nicotinic symptoms).

Despite its proven efficacy in studies26,27, use of oximes has been a matter of debate since early nineties by various studies showing little or no benefit28,29 to harmful effects.30 The disparities are accounted by differences in the lipophilicity, ability of binding with side chains (O'dimethyl vs O'diethyl organophosphates), rate of ageing of complex and insufficient duration or dosing of treatment.

Pawar et al demonstrated reduction in morbidity and mortality in moderately severe cases of acute organophosphorus-pesticide poisoning with high-dose regimen of pralidoxime, consisting of a constant infusion of 1 g/h for 48 h after a 2 g loading dose. They also observed a decrease in total required dose of atropine with institution of continuous infusion.27 Where as in a recent double blinded placebo controlled trial by Eddleston, no improved survival or reduced need for intubation was seen in patients with organophosphorus insecticide poisoning with oxime therapy despite clear reactivation of red cell acetylcholinesterase in diethyl copmpound poisoned patients.30 Chugh et al in a prospective designed study evaluated the role of atropine or atropine plus pralidoxime and concluded that conventional doses of pralidoxime (2g stat followed by 1g every 6 hrly) did not reduce mortality, hospital stay and need for ventilator support.31 Later on comparing the conventional doses of PAM (2g stat followed by 1g every 6 hrly) with the continuous infusion of PAM (2g stat followed by continuous infusion at 10mg/kg/h or to a maximum of 500mg/hr), they could not find any significant difference in terms of survival benefit, need for ventilator support and hospital stay.

WHO recommends the use of pralidoxime with the loading dose of 30 mg/kg over 10-20 min followed by 8-10 mg/kg/hr until clinical recovery or 7 days, whichever is later.32 Singh et al observed improved outcome with continuous PAM therapy, when compared with historical controls, without significant need for mechanical ventilation.33 Alternatively, guidelines laid down by southern hospital network recommends using an initial bolus dose of 2 gm iv ( 30 mg/kg ) over 30 min followed by 1 gm every 8 hourly in mild to moderate poisoning and 500 mg/hr in severe poisoning till clinical recovery (12 - 24 hr after atropine no longer recommended or the patient is extubated) or 7 days whichever is later.13 The later regimen appears to be more promising since rapid and continuous infusion has been reported with hypertension, respiratory failure, cardiac arrhythmias, headache and blurring of vision.30

The Cochrane review on "Oximes for acute organophosphate pesticide poisoning" states, current evidence is insufficient to indicate whether oximes are harmful or beneficial in the management of acute organophosphorus pesticide poisoning, despite strong experimental evidence due to conflicting clinical studies. Based on understanding of the mechanism, in vitro and animal data, theoretically,benefit−risk ratio is more likely to be favourable when they are given early, to patients with serious poisoning by diethyl OPs.34 However, systemic review on oximes did not support WHO recommendations and stated the lack of evidence of oximes in OP poisoning owing to late presentations of patients, use of dimethyl compounds and large intake of poison.The review stressed the need of large scale RCTs to examine other stratigies and regimens.35

The precise treatment protocol of oximes is not well known, but animal studies have shown a level of oximes 4mg /ml to be effective.36 However in severe poisoning (resulting due to large amount of poison) these oximes levels are unlikely to serve the purpose. Therefore, in the absence of consensus, it will be difficult to oppose the recommendations of WHO.


Magnesium: It reduces the Ach release by blocking the presynaptic calcium channels. In addition, it also counteracts the direct inhibitory action of organophosphate compounds on Na+-K+ ATPase pump.37 At a dose of 4 gm/day, it has been shown to reduce the mortality and in hospital stay.

Clonidine: It inhibits the presynaptic synthesis and discharge of Ach and also has adrenergic agonistic action. The effects are more pronounced at central nervous system than peripheral cholinergic synapses.38

Benzodiazepines: They potentiate and facilitate inhibitory GABA neurotransmission and are used for agitated, delirious patients and to control seizures. They also have been reported to reduce respiratory rate in rats and cognitive deficits in primates but no human data is available.39

Sodium Bicarbonate: Animal studies suggest that increasing pH with sodium bicarbonate may reduce mortality rate irrespective of the acidosis40 but no randomized controlled trials are available and further studies are warranted in this regard.

Trihexiphenydyl: This central anticholinergic compound has been tried with good results in cases of delayed encephalopathy (Personal communication). However needs evaluation in trials.

Complications of organophosphate poisoning: In addition to early complications described above, organophosphate compounds lead to late complications which are described as:

Intermediate syndrome (IS): First described in 1974, this neuropathic syndrome is characterized by the development of neuromuscular weakness, after 3-4 days of exposure/resolution of acute cholinergic crisis and appears to result from a combined pre and post synaptic dysfunction of the neuromuscular transmission. Persistent inhibition of nicotinic receptors & structural transformation of Ach receptors have also been suggested as alternate mechanisms.

The features include facial, neck and proximal muscle weakness, cranial nerve palsies, depressed tendon reflexes and respiratory muscle weakness/paralysis. However the primary manifestation is respiratory failure due to weakness of muscles of respiration. Tachypnoea is an important sign & must not be ignored; CO2 retention is a late feature & must not be relied upon. Incidence is reported to be 15% among Indians & it may get complicated by respiratory infections or cardiac arrhythmia. In a retrospective analysis of patients admitted in our ICU, 27% of the patients had IS. The condition can persist for 4-18 days and vary in clinical settings from being self limiting to requirement of mechanical ventilation. Difficulty in weaning from the ventilator, inability to raise head and lift limbs with presence of oculogyric crisis/ extra ocular muscle weakness should raise suspicion of intermediate syndrome. In a prospective study, repetitive nerve stimulation (RNS) changes correlated with the severity of IS. Preceding the onset of IS, decrement-increment pattern was observed at intermediate and high frequencies whereas decrement-increment pattern at low frequencies and severe decrement at higher frequencies with repetitive fades was noted with IS onset.41 Mechanical ventilation remains the main stay of treatment in intermediate syndrome.

Organophosphate induced delayed polyneuropathy (OPIND): It usually occurs 2-3 weeks after large dose of organophosphate poisoning and results due to damage to afferent fibres of the peripheral and central nerves (axonal motor neuropathy) and inhibition of the neuropathy target esterase. The disease is characterized by distal muscle weakness with sparing of cranial nerves, proximal and neck muscles (c.f. intermediate syndrome) and paresthesias of extremities. OPIDN predominantly affect the legs and may last for weeks to months. Treatment is mainly supportive with no definite treatment established till date.


Organophosphate compounds are potent insecticides but are being frequently misused as poisons for self harm. The AchE inhibition by these compounds leads to muscarinic, nicotinic and CNS symptoms. High index of suspicion of organophosphate poisoning, early diagnosis and prompt treatment can be life saving. General supportive measures include decontamination of viscera/skin in contact with poison, maintenance of patent airways with adequate ventilation of the patient. The specific antidote atropine, an antimuscarinic agent is a life saving drug. In addition, other antimuscarinic agents like glycopyrrolate and diphenhydramine also are of proven benefit in organophosphate poisoning. Though oximes have strong theoretical basis for their use, yet evidence regarding its utility in patients of self harm due to OP compounds is conflicting owing to amount of compound ingested, inability to know the chemical nature & late presentation. In addition, the inability to quantify precise doses, monitoring and potential side effects of oximes further pull the hands of clinicians. However, inspite of building evidence against the ineffectiveness of oximes, it seems difficult to go against the current WHO recommendations for their use in OP poisoning for the reasons explained. The use of newer compounds which include magnesium, clonidine, sodium bicarbonate are promising but studies are lacking regarding the use in organophosphate poisoning and large scale trials are needed to further explore their action.