TOXICOLOGY OF AGROCHEMICALS - INSECTICIDES
TOXICOLOGY OF AGROCHEMICALS
The
most widely used agrochemicals of toxicological importance are the pesticides.
With the advent of green revolution, the use of pesticides has been increased
many folds. In addition to agricultural applications, a variety of these agents
are also used to control ectoparasites in birds and animals.
Pesticides include a
large variety of compounds with diverse chemical nature and biological activities.
Generally, on the basis of what pests they destroy, they may be grouped as:
1. Insecticides: agents which destroy
insect pests e.g. Organochlorines (DDT, endrin etc.), organophosphates
(parathion, malathion etc.), carbamates (carbaryl, aldicarb etc.) and
pyrethroids (natural pyrethrins and synthetic pyrethroids such as allethrin,
permethrin etc.).
2. Herbicides/Weedicides: agents which
destroy undesirable herbs/weeds e.g. dinitrophenol, phenoxyacetic acids (2,
4-D), chloroalipathic acids (dalapon), triazenes (atrazine, simazine etc.),
bipyridinium compounds (paraquat, diquat etc.), substituted ureas (monouron,
isoproturon etc.) and substituted dinitroaniline compound (pendimethalin).
3. Rodenticides: agents which destroy
rodent pests e.g. warfarin, ANTU, zinc phosphide, fluoroacetate etc.
INSECTICIDES
Based upon the chemical nature, insecticides
may be categorized into four major groups:
1. Organochlorine insecticides
2. Organophosphate insecticides
3. Carbamate insecticides
4.
Synthetic pyrethroid insecticides
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:
1.
the
DDT group (e.g. DDT, perthane, methoxychlor etc.);
2. the cyclodiene group (e.g. aldrin, dieldrin, endrin, chlordane,
heptachlor, endosulfan etc.); and
3. the miscellaneous group (e.g. toxophene and mirex)
Sources of poisoning
1. Contaminated feed or water.
2. Ingestion of recently pesticide
sprayed foliage or crops.
3. Inhalation or absorption from the
skin during topical application as ectoparasiticides.
Toxicokinetics
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 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.
Mechanism of toxicity
The
chlorinated hydrocarbons are neuro-poisons. By virtue of their 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.
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. 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 progressed into coma. Cholinergic manifestations
like vomiting, marked salivation, mydriasis, diarrhoea and micturition may also
be observed.
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 toxicosis
may produce focal centrolobular necrosis of the liver.
Diagnosis and
differential diagnosis
Based
on the history of exposure to organochlorine insecticides and clinical
symptoms. Organochlorine poisoning should be differentiated from the following poisonings:
Salt
poisoning - history and absence of hyperthermia.
Strychnine
poisoning-convulsions are tonic and absence of behavioural abberations and locomotor
disturbances.
Fluorocaetate-convulsions
not elicited by external stimuli.
Nicotine-only
nicotinic cholinerginc signs are exhibited.
Antichlolinesterase
insecticides-only parasympathetic signs, no behavioural changes.
Lead
poisoning-no abnormal posturing.
Treatment
No
specific antidote is available. Give symptomatic treatment. Rernove the source
of poisoning at once.
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.
A
small dose of atropine sulfate may be given to control the para-sympathetic
signs.
I.V.
calcium borogluconate may be given to prevent liver damage and nullify the
effect of preconvulsive increase in K+ ion concentrations.
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.
Phenobarbital
(10mg/kg/day) may be tried to induce microsomal enzymes and to promote faster
metabolism and excretion.
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.
Organosphosphate 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.) are inactive as such, but are
biotransformed in the body to toxic metabolites e.g. malathion and parathion
converted to malaoxon and paraoxon, respectively.
Sources
of poisoning
Contaminated
feed and water.
Eating of crops/forage
dusted or sprayed with organophosphates.
Spraying or
dusting of the insecticide as ectoparasiticide(s).
Overdosing of
organophosphates when used as systemic antiparasitic agent.
Drinking of
water from empty pesticide container.
Mechanism
of toxicity
Acute organophosphate poisoning is due to irreversible
inhibition of acetylcholinesterase (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 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.
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 phosophorylation 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.
Clinical
symptoms
Clinical signs of organophosphates poisoning are
muscarinic cholinergic, nicotinic cholinergic and CNS symptoms.
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.
Nicotinic cholinergic signs: Muscular
fasciculations, tremors, twitching, spasms, stiff gait or rigid stance due to
hypertonicity of muscles.
CNS signs: Anxiety,
restlessness, hyperactivity and clonic or clonic-tonic convulsions. 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.
Diagnosis
1.History of exposure to
organophosphorus compound.
2.Clinical signs.
3.Post-mortem lesions.
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.
Treatment
1.
Removal of the source of poisoning.
2.
Cholinolytic substance - atropine sulfate 0.2-0.5mg/kg, 1/4th
by IV and 3/4th 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
reactivator 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
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.
Sources of
poisoning Same as those of organophosphates.
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 neuroeffector and
synaptic sites.
Clinical signs
Signs of muscarinic and nicotinic-cholinergic
overstimulations as discussed for organophosphates. Symptoms of muscle weakness
or CNS damage is not usually seen.
Diagnosis
1. History of exposure to carbamates.
2. Clinical signs.
Treatment
Atropine sulfate 0.2-0.5
mg/kg, 1/4th by IV and rest 3/4th by IM.
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.
Sources
of poisoning
Ingestion of pesticide contaminated feeds or water.
Dermal absorption from topical application such as spray
or pour-on to control external parasites.
Mechanism
of toxicity
The synthetic pyrethroid insecticides are neurotoxicants.
The target site of action of pyrethroids is the nerve membrane Na+
channel. Pyrethroids inhibit the Na+ and thereby allowing Na+
current to flow for a prolonged period causing hyperactivity such as hypersensitive
to external stimuli, convulsions and tremors.
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, 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.
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 tremer.
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 hypersalivation, lacrimation, mucoid nasal discharge,
excitement, incoordination, extension of limbs, anorexia and alopecia in
buffalo calves. Pyrethroids may also cause contact dermatitis.
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 organochlorine poisoning.
Treatment
There is no specific antidote.
Treatment is symptomatic.
The animal should be kept calmly.
Sedatives and anticonvulsants (such as barbiturates,
benzodiazepines etc.) to control convulsions.
Mephenesin and atropine sulfate effectively alleviate the
signs of pyrethroid toxicosis in laboratory animals; however, their worthiness
in large animals is not proven.
Gastric lavage.
Soothing skin cream in cases of contact dermatitis.
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