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After reading this article you will learn about the toxicology of various insecticides.
Insecticides:
Based upon the chemical nature, insecticides may be categorized into four major groups:
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1. Organochlorine insecticides (chlorinated hydro carbons)
2. Organophosphate insecticides
3. Carbamate insecticides
4. Synthetic pyrethroid insecticides
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Organochlorine Insecticides:
The organochlorines are the first generation insecticides. They are also known as chlorinated hydrocarbons. These compounds are mainly used as contact insecticides and ectoparasiticides.
The chlorinated hydrocarbons are divided into three groups:
(i) The DDT group (e.g. DDT, per-thane, methoxychlor etc.);
(ii) The cyclodiene group (e.g. aldrin, dieldrin, endrin, chlordane, heptachlor, endosulfan etc.); and
(iii) The miscellaneous group (e.g. toxophene and mirex)
A. Sources of Poisoning:
1. Contaminated feed or water.
2. Ingestion of recently pesticide sprayed foliage or crops.
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3. Inhalation or absorption from the skin during topical application as ectoparasiticides.
Organochlorine insecticides are water insoluble but soluble in oil and solvents and are absorbed rapidly from oily preparations and are capable of penetrating the intact skin when applied in oily solution or emulsion. An exception is the dieldrin, which may be absorbed from dry powder.
However, these compounds, in powder form can easily penetrate the cuticle of insects as compared to mammalian skin and intestinal mucosa which explains its greater toxicity to insects than in mammals. Except methoxychlor, other organochlorine insecticides are stored in the body fat. However, none of these agents are known to accumulate in other vital organs.
B. Mechanism of Toxicity:
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The chlorinated hydrocarbons are neuro-poisons. By virtue of their high lipid solubility, these insecticides can enter the neural membrane. The severe neurological signs of intoxication with DDT in mammals is due to alternation of Na+ channel activity.
The DDT keeps the Na+ channel in the open state for a prolonged period of time causing hyperactivity of the nervous system. Organochlorine insecticides are also reported to suppress GABA and glutamate receptors and voltage activated Ca2+ channels; however, toxicological implication of these actions is yet to be known.
C. Clinical Symptoms:
The first signs of acute toxicosis are behavioural changes characterized by initial anxiety followed by aggressiveness, abnormal posturing, jumping over unseen objects, wall climbing and other madness behaviour.
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Neurological symptoms include hypersensitivity to external stimuli, fasciculation and twitching of facial and eyelid muscles, spasm and twitching of fore and hind quarter muscles, champing of the jaw and hyperthermia. If death does not take place at this stage, the animal may rapidly progress into coma. Cholinergic manifestations like vomiting, marked salivation, mydriasis, diarrhoea and micturition may also be observed.
D. Lesions:
There are no specific major lesions in the nervous system. However, acute aldrin poisoning may cause hepatitis and acute tubular nephrosis. Chronic DDT and methoxychlor toxicoses may produce focal centro-lobular necrosis of the liver.
E. Diagnosis and Differential Diagnosis:
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Based on the history of exposure to organochlorine insecticide(s) and clinical symptoms. Organochlorine poisoning should be differentiated from the following poisonings.
1. Salt poisoning:
History and absence of hyperthermia.
2. Strychnine poisoning:
Convulsions are tonic and absence of behavioural aberrations and locomotor disturbances.
3. Fluorocaetate:
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Convulsions not elicited by external stimuli.
4. Nicotine:
Only nicotinic cholinerginc signs are exhibited.
5. Anticholinesterase insecticides:
Only parasympathetic signs, no behavioural changes.
6. Lead poisoning:
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No abnormal posturing.
F. Treatment:
No specific antidote is available. Give symptomatic treatment.
1. Remove the source of poisoning at once.
2. Control convulsions by barbiturates or benzodiazepines in dogs and cats; and, chloral hydrate or pentobarbital in ruminants. CNS depressants/anesthetics are contraindicated if the animal is already depressed.
3. A small dose of atropine sulfate may be given to control the para-sympathetic signs.
4. IV calcium borogluconate may be given to prevent liver damage and nullify the effect of pre-convulsive increase in K+ ion concentrations.
5. Activated charcoal (900g/cow/day) may adsorb the insecticide that is excreted into the intestine through bile and suppress the enterohepatic circulation of the compound.
6. Phenobarbital (10 mg/kg/day) may be tried to induce microsomal enzymes and to promote faster metabolism and excretion.
G. Analysis:
The insecticides may be detected in ppm concentration in liver and kidney in dead animals and in blood and milk of living animals.
Organophosphorus Insecticides:
The organophosphorus group of pesticides are the second generation insecticides which are employed as contact insecticides and acaricides; animal systemic/topical insecticides and parasiticides; soil nematocides; fungicides ; plant insecticides, insect repellents etc. Some of the commonly employed organophosphorus compounds are malathion (Cythion), fenithrothion (Sumithion), parathion (Thiophos), methyl parathion, phosphamodon, crufomate, chlorpyriphos etc. organophosphate insecticides are of two categories- a directly acting group (e.g. dichlorvos, fenchlorvos, diisopropyl flyrophosphate (DFP), trichlorfan, chlorpyriphos, dimethoate etc.) and an indirectly acting group (e.g. malathion, parathion, fenthion, fenithrothion etc.) which are inactive as such, but are bio-transformed in the body to toxic metabolites e.g. malathion and parathion converted to malaoxon and paraoxon, respectively.
A. Sources of Poisoning:
1. Contaminated feed and water.
2. Eating of crops/forage dusted or sprayed with organophosphates.
3. Spraying or dusting of the insecticide as ectoparasiticide(s).
4. Overdosing of organophosphates when used as systemic anti-parasitic agent.
5. Drinking of water from empty pesticide container.
B. Mechanism of Toxicity:
Acute organophosphate poisoning is due to irreversible inhibition of acetyl cholinesterase (AChE) in places where acetylcholine (ACh) serves as a neurotransmitter. The organophosphorus insecticides interact with the esteratic site of AChE resulting in the formation of a stable enzyme inhibitor complex which does not significantly undergo spontaneous dissociation.
This biochemical interaction caused persistent phosphorylation of the esteratic site of the AChE leading to accumulation of ACh in all cholinergic innervated sites such as neuromuscular junctions, parasympathetic postganglionic terminals in smooth muscles, cardiac muscles and glands; and, in all autonomic ganglia and CNS cholinergic synapses. Hence, all cholinergic (both muscarinic and nicotinic) receptors get overstimulated by accumulated ACh, which in normal course, would have been destroyed, had AChE were not inhibited.
C. Delayed Neurotoxicity:
In addition to acute toxicosis, some organophosphorus compounds (e.g. TOCP, cresyl diphenyl phosphate, haloaxan, fenithrothion, leptophos, chlorpyriphos, trichlorfon etc.) may also cause delayed neurotoxicity in human, chicken, calf, pig, cat, lamb and rabbit. Rat, dog and monkeys are more resistant to delayed neurotoxicity.
The compounds which cause delayed neurotoxicity probably have a common property of binding to specific protein fraction(s) in brain and spinal cord of animals and birds. The organophosphates interact in a specific way with a membrane-bound cell protein referred to as ‘neurotoxic esterase’.
This neurotoxic esterase is present in various sites of the brain, spinal cord and sciatic nerve. The phosphorylation of this esterase is an essential prerequisite for the development of neurotoxicity induced by organophosphates.
Delayed neurotoxicity is characterized by degeneration of motor nerve axons, starting at the periphery and thereby following the motor nerves into the spinal cord and up into the spinocerebellar, vestibulospinal and other tracts. The clinical signs appear after the degenerated axons became demyelinated. However, the chain of events from the alteration of neurotoxic esterase to degeneration of nerve axon if not fully understood.
D. Clinical Symptoms:
Clinical signs of organophosphates poisoning are muscarinic cholinergic, nicotinic cholinergic and CNS symptoms.
1. Muscarinic cholinergic signs:
profuse salivation, lacrimation, nasal discharge, respiratory sounds due to bronchoconstriction and excess bronchial secretions, pronounced GI sounds, colic and diarrhoea, bradycardia, miosis ; sweating, coughing, vomiting and frequent micturition.
2. Nicotinic cholinergic signs:
Muscular fasciculations, tremors, twitching, spasms, stiff gait or rigid stance due to hyper-tonicity of muscles.
3. CNS signs:
Anxiety, restlessness, hyperactivity and clonic or clonic-tonic convulsions.
E. Lesions:
No lesions are seen if the animal dies quickly. However, animals dying after several hours of toxicosis may show pulmonary oedema and congestion, cyanosis, hemorrhages on heart or other organs and skeletal muscles. In delayed neurotoxicity, degeneration and demyelination of peripheral and motor neurons may be noted.
F. Diagnosis:
1. History of exposure to organophosphorus compound.
2. Clinical signs.
3. Post-mortem lesions.
G. Differential Diagnosis:
Organophosphate poisoning should be differentiated from carbamates and organochlorines poisoning. Carbamate poisoning is less severe in nature as it reversibly inhibited the AChE. In organochlorine poisoning, there is hyperthermia and behavioural abberations.
H. Treatment:
1. Removal of the source of poisoning.
2. Cholinolytic substance-atropine sulfate 0.2-0.5 mg/kg, one-fourth by IV and three-fourth by IM or SC routes every 3-6 hours for 24 hours.
3. Cholinesterase reactivators regenerate the phosphorylated AChE. Oximes reactivators after combining with the anionic site of AChE exert a nucleophilic attack on the phosphorus of insecticide. The oxime phosphate complex is then split off leaving behind the regenerated AChE enzyme. 2-PAM (2-pyridine aldoxime methiodide ; Pralidoxime), an oxime cholinesterase re-activator may be given at the dose rate of 20-50 mg/kg as 10% solution by IM route or by slow IV injection in small animals. In large animals, a dose of 25-50 mg/kg as 20% solution may be given by slow IV injection. At any cost, the maximum dose should not exceed 100 mg/kg. This treatment may be repeated, if required.
The other oximes available are obidoxime, diacetyl monoxime (DAM) and monoisonitrosamine (MINA).
4. Supportive therapy.
I. Analysis:
The organophosphorus compounds are non-persistent in the body tissues as they are rapidly metabolized by the liver. Even fresh tissues, blood, urine and milk may give negative results.
However, AChE activity is a confirmatory index of organophosphate poisoning. Inhibition of blood AChE activity by 25% from normal indicates exposure to organophosphorus compounds.
Carbamate Insecticides:
Carbamates are the third generation insecticides and are used against a wide variety of pests as the organophosphorus compounds. Some of the commonly employed carbamates are aldicarb, carbufuran, carbaryl (Sevin), aminocarb etc.
A. Sources of Poisoning:
Same as those of organophosphates.
B. Mechanism of Toxicity:
Carbamates are reversible inhibitors of AChE. These insecticides interact with both anionic and esteratic sites of AChE and reversibly carbamylate the esteratic site. However, AChE is capable of hydrolyzing carbamate insecticides. Therefore, poisoning develops only when the carbamates present in the body is quite large that the rate of carbamylation of AChE exceeds the rate of hydrolysis of the insecticide by AChE. Signs of toxicosis are manifested when ACh starts accumulating in the neuro-effector and synaptic sites.
C. Clinical Signs:
Signs of muscarinic and nicotinic-cholinergic over-stimulations as discussed for organophosphates. Symptoms of muscle weakness or CNS damage is not usually seen.
D. Diagnosis:
1. History of exposure to carbamates.
2. Clinical signs.
E. Treatment:
Atropine sulfate 0.2-0.5 mg/kg, one-fourth by IV and rest three- fourth by IM or SC route.
2-PAM is contraindicated in carbamate poisoning because it may worsen the condition.
Pyrethrins and Synthetic Pyrethroid Insecticides:
Pyrethroids are the fourth generation insecticides:
Pyrethrins are natural insecticides obtained from the flowers of Chrysanthemum cinerariaefolium and C. roseum. The synthetic pyrethroids are structurally related directly or indirectly to natural pyrethrins.
There are two different groups of synthetic pyrethroids:
(i) Non-cyano containing pyrethroids or type I pyrethroids e.g. allethrin, permethrin, cismethrin, bioresmethrin etc. and
(ii) Cyano containing pyrethroids or Type II pyrethroids e.g. deltamethrin, cypermethrin, fenvalerate etc.
Pyrethroids are widely used insecticides against a variety of pests of agricultural, veterinary and public health importance. These insecticides have low mammalian toxicity. They are also rapidly metabolized and excreted.
A. Sources of Poisoning:
1. Ingestion of pesticide contaminated feeds or water.
2. Dermal absorption from topical application such as spray or pour- on to control external parasites.
B. Mechanism of Toxicity:
The synthetic pyrethroid insecticides are neuro-toxicants. The target site of action of pyrethroids is the nerve membrane Na+ channel. Pyrethroids inhibit the Na+ inactivation and thereby allowing Na+ current to flow for a prolonged period causing hyperactivity such as hypersensitive to external stimuli, convulsions and tremors.
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Pyrethroids without an alpha-cyano group (permethrin, allethrin, cismethrin etc.) cause a moderate prolongation of transient increase in Na+ permeability of the nerve membrane during depolarization resulting in passage of short trains of repetitive nerve impulses in sense organs, sensory nerve fibres and nerve terminals.
Whereas, the alpha-cyano containing pyrethroids (deltamethrin, cypermethrin, fenvalerate etc.) produce long lasting prolongation of the transient increase in Na+ permeability of the nerve membrane during excitation leading to passage of long lasting trains of repetitive impulses in sense organs and a frequency dependent depression of the nerve impulse in nerve fibers.
C. Clinical Symptoms:
The clinical signs of acute type I pyrethroid poisoning in laboratory animals are restlessness, incoordination, hyperactivity, tremor, prostration and paralysis. The Type I pyrethroids-induced tremor is referred to as ‘T- syndrome’. Rats exhibiting ‘T-syndrome’ show aggressive behaviour and hypersensitivity to external stimuli. The body temperature is appreciably increased during poisoning which is probably due to increased muscular acitivity associated with tremor.
The Type II pyrethroids cause burrowing behaviour, clonic siezures, writhing and profuse salivation also referred to as choreoathetosis/salivation or ‘CS-syndrome’ in laboratory animals. In large animals, fenvalerate is capable of inducing restlessness, frothing of the mouth, dyspnea, erection of ear and tail, mydriasis, regurgitation of ruminal contents, incoordination, tremor, clonic convulsions and recumbency.
Deltamethrin spray causes hyper-salivation, lacrimation, mucoid nasal discharge, excitement, incoordination, extension of limbs, anorexia and alopecia in buffalo calves. Pyrethroids may also cause contact dermatitis.
D. Diagnosis and Differential Diagnosis:
Diagnosis may be based on the history of exposure to pyrethroids and clinical signs exhibited by the poisoned animals. Almost identical signs are also seen in organo-chlorine poisoning.
E. Treatment:
There is no specific antidote. Treatment is symptomatic.
1. The animal should be kept calmly.
2. Sedatives and anticonvulsants (such as barbiturates, benzodiazepines etc.) to control convulsions.
3. Mephenesin and atropine sulfate effectively alleviate the signs of pyrethroid toxicosis in laboratory animals; however, their worthiness in large animals is not proven.
4. Gastric lavage.
5. Soothing skin cream in cases of contact dermatitis.