Organophosphorus Insecticides

Background

• Pesticides are substances or mixtures that prevent, destroy, repel, or mitigate pests.
• Pests include insects, rodents, weeds, etc.
• Pesticides can be insecticides (insects), herbicides (weeds) and fungicides (fungi and molds).
• Pesticides can also be rodenticides (rodents), acaricides (mites), molluscides (snails and other mollusks), miticides (mites), larvicides (larvae), and pediculocides (lice).
• Plant growth regulators, repellants (pheromones), and attractants also classified as pesticides.

Organophosphorus Insecticides

• Organophosphorus (OP) insecticides have a general structure represented by R1, R2, P, O/S, and X.
• X is a leaving group displaced when the OP phosphorylates acetylcholinesterase (AChE).
• X is sensitive to hydrolysis.
• R1 and R2 are alkoxy groups or chemical substituents; either oxygen or sulfur.
• OPs are divided into subclasses like phosphates and phosphorothioates based on chemical differences.

Biotransformation of OPs

• Compounds with sulfur bound to phosphorus need metabolic bioactivation for biological activity.
• Compounds with a P=O moiety are effective AChE inhibitors.
• Oxidative desulfuration and thioether oxidation are catalyzed by cytochrome P450s.
• Catalytic hydrolysis by A-esterases detoxifies OPs.
• Serine esterases classified as B-esterases phosphorylate compounds, leading to non-catalytic hydrolysis of OPs.

Toxicity, Signs, Symptoms, Mechanism of Action

• Insecticides are acutely toxic, with oral LD50 values (rat) often below 50 mg/kg.
• Acute dermal toxicity is high for some OPs.
• Inhibition of AChE by OPs leads to acetylcholine accumulation at cholinergic synapses.
• Overstimulation of muscarinic and nicotinic cholinergic receptors occurs because of AChE inhibition by OPs.
• Cholinergic syndrome includes increased sweating, salivation, bronchial secretion.
• Other symptoms include bronchoconstriction, miosis, gastrointestinal motility increase, diarrhea, tremors.
• Severe OP poisoning's hallmark is respiratory failure.
• Mild poisoning/early-stage severe poisoning may have no clear symptoms.

OPs Affect on Enzymes

• OPs with a P=O moiety phosphorylate hydroxyl groups on serine, impeding enzyme action.
• Phosphorylated AChE is slowly hydrolyzed by water.
• The rate of "spontaneous reactivation" depends on the chemical nature of the R substituents.
• Reactivation of phosphorylated AChE doesn't occur after the enzyme-inhibitor complex has "aged".
• Aging is the loss of alkyl (R) groups via non-enzymatic hydrolysis.
• Phosphorylated AChE is irreversibly inhibited once aged.
• Replacing enzyme activity requires new enzyme synthesis, which can take days.

Intermediate Syndrome

• Intermediate syndrome is a manifestation of OP exposure seen in 20-50% of acute OP poisoning cases.
• The syndrome develops 1-several days post-poisoning.
• The syndrome starts during recovery from or after cholinergic manifestations or cholinergic crisis.
• Features include weakness of respiratory, neck, and proximal limb muscles.
• Mortality is high due to paralysis, ranging from 15-40%, with up to a 30-day recovery.
• The syndrome is not an effect of AChE inhibition.
• The precise mechanisms are not fully known.
• The hypothesis that muscle weakness results from nicotinic receptor desensitization due to prolonged cholinergic stimulation is considered valid.

Organophosphate-Induced Delayed Polyneuropathy (OPIDP)

• Some OPs may cause OPIDP.
• Symptoms of OPIDP include tingling in hands and feet, followed by sensory loss.
• Other symptoms include progressive muscle weakness, flaccidity in distal skeletal muscles, and ataxia.
• OPIDP Symptoms may occur 2-3 weeks after a single exposure, when acute cholinergic and intermediate syndromes have subsided.
• OPIDP is classified as a distal sensorimotor axonopathy

OPIDP Studies

• Neuropathological studies find the primary lesion a degenerative change in distal levels of axons and their terminals.
• The primary lesion primarily affects larger/longer myelinated central and peripheral nerve fibers.
• The lesion leads to the breakdown of neuritic segments and myelin sheaths.
• Aging of neuropathy target esterase (NTE) is involved in OPIDP.
• The details of phosphorylation, NTE aging, and axonal degeneration are not fully understood.

Carbamates and Toxicity

• Carbamate insecticides are derived from carbamic acid and are mainly N-methylcarbamates.
• Acute oral toxicity ranges from moderate to low, such as carbaryl, to extremely high, such as aldicarb.
• Dermal skin penetration by carbamates is increased by organic solvents and emulsifiers in formulations.
• Carbamates are susceptible to enzyme-catalyzed biotransformation, including oxidation and hydrolysis.
• The toxicity mechanism of carbamates is AChE inhibition.
• The toxicity is rapidly reversible.

Carbamates and Poisoning

• Symptoms include miosis, urination, diarrhea, salivation, muscle fasciculation, and CNS effects.
• Acute intoxication resolves within hours.
• Treatment relies on atropine.
• Carbamates inhibit neuropathy target esterase (NTE).
• Carbamylated NTE cannot age/initiate OPIDP when given before causing a neuropathic organophosphate.
• Carbamates offer protection against OPIDP when given after, they can promote OPIDP.

Pyrethoids

• Pyrethrins are used for insecticides since they decompose rapidly on exposure to light
• Pyrethroids that are synthetic are commonly used for Topical treatments
• Pyrethroids alter function of insect nerves by modifying kinetics of voltage-sensitive sodium channels.
• Pyrethroids can increase the sodium permeability of the nerve membrane that underlies the nerve action potential.
• Pyrethroids are metabolized through hydrolysis of the ester linkage by hepatic and plasma carboxylesterases.
• Pyrethroids are metabolized through by oxidation of the alcohol moiety by cytochrome P450s.
• Further reactions of pyrethroids include oxidations, hydrolysis, and conjugation.
• Toxic signs in rats are divided into two types - Type I and Type II.

Pyrethoid Types

• Type I compounds produce behavioral arousal, aggressive sparring, and startle.
• The effects from type I compounds progresses to whole-body tremor and prostration.
• Type II compounds produce profuse salivation, coarse tremor and choreoathetosis.
• Type II can progress to clonic seizures.
• Pyrethroids disrupt voltage-gated sodium channels in mammals and insects.
• Pyrethroids slow the activation and rate of inactivation of the sodium channel, leading to hyperexcitability.
• Type II pyrethroids bind to and inhibit GABAA-gated chloride channels to affect sodium channels.
• The effects contributed to seizures in severe type II pyrethroid poisoning.

Effects from Pyrethoids

• occupational exposure can result to contact to dermal
• Symtoms can include tingling or pricking when its severe it can get hot burning.
• Condition is reversed in 24 hours
• When you apply topical E vitamins its effective.
• High levels can cause slight liver enlargement with histopathologic changes.
• There is slight teratogenicity but there is some mutagenicity
• High doses in rodents can cause increased lymphoma incidence but its not definite.

Organo-chlorine Insecticides

• These include Chlorinated Ethane Derivatives (DDT) the cyclodienes etc
• The toxicity is acute toxicity, with some chronic exposure.
• exposure can lead to adverse health effects.
• DDT and analogs are effective against agricultural pests and transmit diseases.
• DDT has slight oral toxicity and only limited dermatological.
• Humans doses can produces illness
• Toxicity from dermatological is low
• DDT is found in adipose tissue in the body, and its excreted through bile ducts.
• DDT Causes hyper susceptibility to ear etc.
• can cause eventual motor unrest
• Death is always caused by respiratory failure.

Toxicity from DDT

• The earliest symptoms from DDT is parathesia
• Dizziness and vomit also known side effects.
• The important is that DTT causes problems in the liver.
• DDT breakdown results in a high increase in liver weight.
• the breakdown of DDE and DDD are carcinogenic in rodents with potential for increase in tumor size.

Other insectides

• The best abundant is rotenone which is used as insecticide in agriculture particularly in farming.
• Is is known that both targeted species and none targeted species from rotenone is due to its ability to inhibit.
• It works by blocking the electron transport and poisoning
• Can cause Muscular Depression.
• Rotenone can possibly lead to Parkinson diesease.