PESTICIDE AND INSECTICIDE

Prepared BY-R.R.

Pesticide

 Pesticides can be defined as any substance or mixture of substances intended for preventing, destroying,
repelling, or mitigating pests. Pests can be insects, rodents, weeds, and a host of other unwanted organisms.

 Ideally, their injurious action would be highly specific for undesirable targets; in fact, however, most
pesticides are not highly selective, but are generally toxic to many nontarget species, including humans.

 The use of pesticides must take into consideration the balance of the benefits that may be expected versus
the possible risks of injury to human health or degradation of environmental quality.

 Workers involved in the production, transport, mixing and loading, and application of pesticides, as well as
in harvesting of pesticide-sprayed crops, are at highest risk for pesticide exposure.

 The dermal route is thought in this case to offer the greatest potential for exposure, with a minor contribution
of the respiratory route when aerosols or aerial spraying are used

Human Poisoning

 In the general population and in occupationally exposed workers, a primary concern relates to a possible
association between pesticide exposure and increased risk of cancer.

 Some pesticides may act as endocrine disruptors, possibly contributing to various adverse effects in humans,
including cancer and reproductive and developmental toxicity.

 WHO estimated that there are around three million hospital admissions for pesticide poisoning each year,
which results in around 220,000 deaths (WHO, 1990).

 Most occur in developing countries, particularly in Southeast Asia, and a large percentage is due to
intentional ingestion for suicide purposes.

 Among 74 active ingredients listed in Class 1A (Extremely hazardous) and Class 1B (Highly hazardous),
48 (65%) are insecticides, in particular organophosphates.

 Herbicides, again as a class, have generally moderate to low acute toxicity, one exception being paraquat
(which has a low dermal toxicity but causes fatal effects when ingested).

 Fungicides vary in their acute toxicity, but this is usually low.

 Insecticides play a most relevant role in the control of insect pests, particularly in developing countries. All
of the chemical insecticides in use today are neurotoxicants, and act by poisoning the nervous systems of
the target organisms.

Organophosphorus Compound

 The chemistry of organic phosphorus (OP) has been thoroughly investigated (Chambers et al., 2001). The
general structure of OP insecticides can be represented by
 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 and R2 are most commonly alkoxy groups (i.e., OCH3 or OC2H5).

PATHOPHYSIOLOGY

1. Inhibit the function of carboxylic ester, hydrolases such as chymotrypsin, ACHE, BUCHE
(pseudocholinesterase), plasma and hepatic carboxylesterases and other nonspecific esterases within the
body.

2. Acetylcholine stimulates Ca-mediated ACh release at the nerve terminal. It binds with postsynaptic
receptors via G-protein (muscarinic) and ligand-linked ionic channels (nicotinic): Then alter the flow of K,
Na+, Ca2+, and change membrane permeability: Propagate action potential.

3. AChE breaks down ACh to acetate and choline and terminates the effects of ACh binding within the
synaptic cleft.

4. AChE-Inhibitor stops the breakdown and accumulates Ach

5. Depolarization occurs and causes paralysis.

Organophosphate and Carbamate

Both organophosphates and carbamates can bind into an acyl pocket at the active site of AChE and change the
configuration of enzyme molecule (by binding of phosphate and carbamoyl group to the serine amino acid at
the active site of Ach) and prevent its function

Organophosphates permanently alter the shape of the acyl pocket which causes hydrolysis of the serine-
phosphate bond. For this, the antidote function becomes limited. This permanent change is called 'aging'.
Carbamates dissociate from AChE within 24 hrs. So, they do not cause aging. Carbamates do not cross BBB
and have CNS toxicity. But their peripheral toxicity is identical.
Toxicity of Organophosphates and Carbamate

Inhibition of AChE causes accumulation of acetylcholine at cholinergic synapses, with overstimulation of

cholinergic receptors of the muscarinic and nicotinic type.

▪ Acute toxicity

As these receptors are localized in most organs of the body, a "cholinergic syndrome" ensues, which
includes

➢ increased sweating, salivation, and lacrimation

➢ profound bronchial secretion,
➢ bronchoconstriction,
➢ miosis,
➢ increased gastrointestinal motility, diarrhea,
➢ tremors,
➢ Muscular twitching, and various central nervous system effects (Table 22-9).
 Receptor Type System / Organ Effects

Muscarinic Receptors Cardiovascular • Bradycardia

• Hypotension

Respiratory • Rhinorrhoea
• Bronchorrhoea (BBC)
• Bronchospasm
• Cough

Gastrointestinal • Nausea / Vomiting

• Increased salivation
• Abdominal cramps
• Diarrhea
• Fecal incontinence
Genitourinary • Urinary continence

Eyes • Blurred vision

• Increased lacrimation

Nicotinic Receptors Cardiovascular • Tachycardia

• Hypertension

Musculoskeletal • Weakness
• Fasciculations
• Cramps
• Paralysis
Central Receptors General Effects • Convulsions
• Restlessness
• Ataxia
• Dysarthria
• Tremors
• Coma
• Absent reflexes
• Respiratory depression
• Circulatory collapse

Death occurs, due to respiratory failure due to

1. inhibition of respiratory centers in the brain stem,

2. bronchoconstriction bronchial secretion, and
3. flaccid paralysis of respiratory muscles and increased

Toxicity of Organophosphates and Carbamate

Organophosphate-induced delayed Polyneuropathy OPs may also. cause another type of toxicity, known as
organophosphate- induced delayed polyneuropathy (OPIDP). Signs and symptoms include tingling of the hands
and feet, followed by sensory loss, progressive muscle weakness and flaccidity of the distal skeletal muscles of
the lower and upper extremities, and ataxia Long-Term Toxicity Chronic exposure has been associated with
neurobehavioral abnormalities, particularly at the cognitive level
 Treatment of Organophosphates and Carbamate poisoning

1. Penetrate through the skin or normal latex gloves or polyvinyl gloves, so nitrile or neoprene (chemical
recommended.
2. In case of dermal exposure, contaminated clothing should be removed, and the skin washed with
alkaline soap.
3. Aspiration of gastric contents through nasogastric tube should be done if ingested with past hour.
4. Use activated charcoal is also recommended of in case of ingestion
5. Diazepam (10-20 mg) is also used in the treatment of acute OP poisoning to

 relieve anxiety in mild cases,

 reduce muscle fasciculations and
 antagonize convulsions in more severe cases
6. Oximes, such as pralidoxime (2-PAM) are used in the therapy of OP poisoning.

2-PAM contains a positively charged atom capable of attaching to the anionic site of AChE, and facilitate
dephosphorylation of the enzyme (Fig. 22-4), thus restoring the catalytic site of AChE to its function. This
chemical reaction occurs only when the phosphorylated AChE has not undergone aging.

Act as a scavenger for non-bound organophosphates. It can cause neuromuscular blockage if administered
too rapidly

Dose: pralidoxime chloride, an initial 1 g dose given intravenously is recommended, followed after 15-30
minutes by another 1 g if no improvement is seen. If still no improvement is seen, an infusion of 0.5 g/h

can be started.

Pyrethrins / Pyrethroids

 Pyrethrins were first developed as insecticides from extracts of the flower heads of Chrisanthenum
cinerariaefolium, whose insecticidal potential was appreciated in ancient China and Persia.

 Pyrethrins refer to six active compounds found in pyrethrums

 Pyrethrin I, Pyrethrin II, Jasmolin I, Jasmolin II, Cinerin I and Cinerin II

 In the past thirty years and now accounted for more than 25% of the global insecticide market.

 Pyrethroids are synthetic derivatives of pyrethins and used widely as insecticides both in the house and in
agriculture,

- in medicine for the topical treatment of scabies and head lice, and
 - in tropical countries in soaked bed nets to prevent mosquito bites.

Pathophysiology

 Immediate and delayed hypersensitivity reaction.

 Increase bronchial reactivity to histamine and other mediators through mast cells.

Mechanism of Action

 Pyrethroids are known to alter the normal function of insect nerves by delaying closure of inwards voltage-
sensitive sodium channels, which mediate the transient increase in the sodium permeability of the nerve
membrane that underlies the nerve action potential.

 That increase neurotransmitter release

 Hypersensitivity to sensory stimuli occur

Clinical presentation of Pyrethrins/ Pyrethroids

Pyrethrins toxicity

1. Allergic rhinitis
2. Contact dermatitis
3. Asthma
4. Hypersensitivity pneumonitis

Pyrethroids toxicity

1. Paresthesias, dizziness, headache

2. Chest tightness, Palpitation, Blurred vision
3. Abdominal pain, nausea, vomiting
4. Abnormal cutaneous sensation which is described as stinging or burning sensation and progresses to
numbness of the lip and tongue
Treatment of Pyrethrins/Pyrethroids

For children

1. Small ingestion does not require GI- decontamination. Large ingestion required GI- decontamination.
2. Aspiration with a nasogastric tube is enough.
3. Antihistamine (Diphenhydramine 25-50 mg orally or IV OR IM route).

For severe allergic reaction

1. Oxygen, epinephrine, or bronchodilator necessary

2. For dermal washing with soap and water.
3. Gl-decontamination with activated charcoal
4. 1 g/kg.

5. Anticonvulsant
a. Diazepam: 5-10 mg IV for adult
0.1-0.2 mg/kg child
Or
b. Lorazepam 2-4 mg IV for adult
c. Phenobarbital - 10-20 mg/kg

Organochlorine Compounds

1. The organochlorine insecticides include the chlorinated ethane derivatives, such as DDT and its analogs.

2. DDT is the universally accepted common name of the insecticide.

3. DDT has moderate acute toxicity when given by the oral route.

4. In humans, oral doses of 10-20 mg/kg produce illness, but doses as high as 285 mg/kg have been ingested
accidentally without fatal results.

5. Toxicity from dermal exposure in humans is also low.

6. Upon absorption, DDT distributes in all tissues, and the highest concentrations are found in adipose tissue.
DDT is also extensively but slowly metabolized.

DDT [1,1,1-trichloro-2, 2-bis (4-chlorophenyl) ethane] Acute exposure to high doses of DDT causes

· motor unrest, increased frequency of spontaneous movements,

· abnormal susceptibility to fear and

· hyper-susceptibility to external stimuli (light, touch, sound).

· This is followed by the development of fine tremors and eventually tonic-clonic convulsions.

· Symptoms usually appear several hours after exposure, and death, due to respiratory failure, may follow after
24-72 hours.
· In humans, the earliest symptom of poisoning by DDT is hyperesthesia of the mouth and lower part of the
face, followed by paresthesia of the same area and of the tongue.

· Dizziness, tremor of the extremities, confusion and vomiting follow, while convulsions occur only in severe
poisoning.

Chronic exposure

 An important target for DDT is the liver.

 DDT and DDE increase liver weight and cause hepatic cell hypertrophy and necrosis, and are potent
inducers of cyt P450, particularly CYP2B and CYP3A.

Endocrine Disruption

 An endocrine, or hormone, disruptor can be defined as an exogenous chemical that interferes with the
synthesis, secretion, transport, binding, action or elimination of natural hormones in the body, that are
responsible for the maintenance of homeostasis, reproduction, development and behavior.

 Several pesticides may fall into this category, and among these, a large number are organochlorine
insecticides. DDT has estrogenic properties, it can act as an agonist at estrogen receptors a &ß.

 Chlordecone also has estrogenic properties. Other organochlorine compounds with weak estrogenic activity
are dieldrin, endosulfan, toxaphene, lindane and the ẞ isomer of hexachlorocyclohexane (BBHC).

DEET (N,N-diethyl-m-toluamide or N,Ndiethyl-3-methyl benzamide)

 DEET is very effective at repelling insects, flies, fleas, and ticks, and protection time increases with
increasing concentrations.

 DEET undergoes oxidative biotransformation catalyzed by various cytochromes P450, and is excreted
mostly in the urine.

Pathophysiology

 The most common symptoms were seizures. Seizure disorders occur in 3-5% of children.

 Dose related hypotension and bradycardia by increase cardiac output

 Increase serum ammonia level.

Toxicity

· Confusion
· Ataxia
· Generalized seizure
· Encephalopathy
Treatment

Dermal, ocular, and gastric decontamination ✓ Activated charcoal for ingestion

Seizures: IV benzodiazepines, phenytoin or phenobarbital

Bipyridil Compounds (Paraquat and Diquat)

 Herbicides are chemicals that are capable of either killing or severely injuring plants.

 Paraquat has one of the highest acute toxicity among herbicides.

 Paraquat can be reduced to form a free radical, which in the presence of oxygen, rapidly reoxidizes to the
cation, with a concomitant production of superoxide anion
(02-).

 Thus, once paraquat enters a cell, it undergoes alternate reduction followed by reoxidation, a process known
as redox cycling.

 Superoxide dismutase (SOD) are a family of metallo-enzymes that can dismutate superoxide anions to
hydrogen peroxide and oxygen.

 Three hypotheses have been proposed to account for the ensuing cytotoxicity. The generation of superoxide
anion and subsequently of hydroxy radicals would initiate lipid peroxidation, ultimately leading to cell
death.

 Intracellular redox cycling of paraquat would also result in the oxidation of NADPH, leading to its cellular
depletion, which is augmented by the detoxification of hydrogen peroxide formed in the glutathione
peroxidase/ reductase enzyme system to regenerate GSH (Fig. 22-19).

 A third hypothesis is that paraquat toxicity is due to mitochondrial damage.

Paraquat Toxicity

1. Paraquat and diquat undergoes cyclic reduction/oxidation in conjugation with NADPH and oxygen,

2. Di-cationic bipyridyls are reduced by NADPH to mono-cationic free radicals and cyclically return to their
original form by giving up an electron to oxygen to form superoxide radicals (0,) which then form hydrogen
peroxide.

3. Formation of hydroxyl radicals leading to lipid peroxidation and cell death.

4. DNA and protein are also destroyed.

5. Detoxication of H2O, via glutathione

bipyridyls are caustic and produce injury in contact with skin, eyes, and mucus membranes. Major target organs
are GIT, kidney, and lung.

 Upon acute exposure to lethal doses of paraquat, mortality may occur 2-5 days after dosing, though death
can also occur after longer periods.

 Damage to alveolar epithelial cells is seen within 24 hours after exposure.

 Damage progresses in the following 2-4 days with large areas of the alveolar epithelium completely lost.
This is followed by

- alveolar edema,
- extensive infiltration of inflammatory cells into alveolar interstitium,
- and finally death due to severe anoxia
 1. Mild toxicity (dose < 20 mg/kg)
- No or mild GIT symptoms

2. Moderate toxicity (dose 20-40 mg/kg)

 Local damage on GIT include
a. Orthopharynx
b. severe vomiting
c. Gl-bleeding

 Early phase complication

a. Pneumomediastinum (abnormal air is present in the mediastinum thorax)

b. Pneumothorax
c. Renal failure gradually occur
d. Pulmonary fibrosis after day or weeks
e. Death occurs in majority of persons with 20-40 mg/kg ingestions of paraquat

➢ Severe toxicity (dose 20-40 mg/kg)

 Multisystem organ failure
 Caustic mucus membrane damage
 Vomiting
 Massive myonecrosis (destruction of muscle tissue)
 Renal, hepatic, respiratory, cardiac, neurologic, adrenal or pancreatic failure
 Death within hours to a few days

Treatment of Paraquat

1. Airway management and advice life support

2. Decontamination
3. GI multidose activated charcoal 1 mg/kg PO. Copious irrigation

4. IV crystalloids (Normal saline 0.9 NaCl solution, Ringer lactate) to maintain urine output at 1-2 ml/kg/hr.

5. Oxygen for hypoxia

6. Analgesic and anxiolytic drug
7. Extracorporeal removal

8. Hemoperfusion
9. Hemodialysis only for renal failure
10. Peritoneal dialysis