1. TOXICITY OF PESTICIDES

2. Pesticide is is consisted of 2 parts:
Pest = unwanted creature or living
Cide = killing or elimination
“Any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any insects, rodents, nematodes, fungi, or weeds, or any other forms of life declared to be pests”
Federal Insecticide, Fungicide, and Rodenticide Act (US EPA)

3. Classification of Pesticides
Target organism: (e.g., herbicides, insecticides, fungicides, rodenticides, pediculicides,…
Chemical Structure: organic, inorganic, synthetic, biological (biopesticide).
According to effects on human health (recommended by WHO): based on acute risk to human health (that is the risk of single or multiple exposures over a relatively short period of time).

4. ORGANOPHOSPHATE TOXICITY
Garden and household pesticides.
Formulations; liquids, sprays, powders.
In veterinary medicine they are found in pedicullicide lotions.
Shampoos, aqueous and alcoholic lotions are also used as human pedicullicides and scabicides.
Organophosphate nerve agents may be used as chemical warfare agents. sarin used in the Tokyo subway attacks of 1995.
Parathion: widely used in Libya.

5. Organophosphate Toxicity
Carbamate Toxicity

6.
organophosphates and carbamates exhibit similar clinical manifestations with toxicity and require similar management

7. Organophosphates have been used as insecticides worldwide for more than 50 years.
Worldwide, an estimated 3,000,000 people are exposed to organophosphate or carbamate agents each year, with up to 300,000 fatalities
Toxicity generally results from accidental or intentional ingestion of, or exposure to, agricultural pesticides.
Other potential causes of organophosphate or carbamate toxicity include ingestion of contaminated fruit, flour, or cooking oil, and wearing contaminated clothing

8. Mechanism of Toxicity inhibition of Ach-Esterase enzyme
OP phosphorylate serine hydroxyl group at the site of action of acetylcholine.
Once OP binds to AChE, the enzyme can undergo one of the following:
Endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases
Reactivation by antidote pralidoxime (2-PAM)
Irreversible binding and permanent enzyme inactivation (aging phenomenon)
Acuumulated Ach activate muscarinic, nicotinic, CNS receptors

9. Partially electropositive phosphorus is attracted to partially electronegative serine
Breakdown of acetylcholine

10. Cholinesterase inhibitor attached to acetylcholinesterase preventing the attachment of acetylcholine

11. Dr. TAHAR ABDULAZIZ MD, PhD
Mechanism of Toxicity
Excess ACh in the synapse can lead to 3 sets of symptoms and signs:
At postganglionic muscarinic synapses lead to SLUDGE/BBB.
At nicotinic motor end plates causes persistent depolarization of skeletal muscle resulting in fasciculations, progressive weakness, and hypotonicity.
OP cross the blood-brain barrier, they may cause seizures, respiratory depression, and CNS depression for reasons not completely understood.
OP bind to RBC cholinesterase & plasma cholinesterase (pseudocholinesterase) in the serum.
The kinetics of the enzyme will reach zero within 10 hours i.e. all enzyme will be in the form of OP-AchE complex, this situation is called aging phenomenon.
Dr. TAHAR ABDULAZIZ MD, PhD

12. Dr. TAHAR ABDULAZIZ MD, PhD

13. Dr. TAHAR ABDULAZIZ MD, PhD

14. Clinical Manifestations
Pesticides can rapidly be absorbed through the skin, lungs, GI tract, and mucous membranes.
Symptoms usually occur within a few hours after GI ingestion and appear almost immediately after inhalational exposure.
Dr. TAHAR ABDULAZIZ MD, PhD

16. Clinical Features
The dominant clinical features of acute cholinergic toxicity include
bradycardia, miosis, lacrimation, salivation, bronchorrhea, bronchospasm, urination, emesis, and diarrhea.
Diaphoresis may occur because sweat glands are regulated through sympathetic activation of postganglionic muscarinic receptors.
At times, however, mydriasis and tachycardia may be observed, as sympathetic ganglia also contain nicotinic receptors

17. cholinergic toxic syndrome
1- Muscarinic effects: SLUDGE/BBB mnemonic
S = Salivation L = Lacrimation U = Urination
D = Defecation G = GI symptoms E = Emesis
B = Bronchorrhea B = Bronchospasm B = Bradycardia
2- Nicotinic effects at neuromuscular junctions and autonomic ganglia: weakness, fasciculations, and paralysis.
3- CNS effects may lead to seizures and CNS depression.
Dr. TAHAR ABDULAZIZ MD, PhD

18. Cardiac issues
 Cardiac arrhythmias, including heart block and QTc prolongation, are occasionally observed in organophosphorus agent poisoning.
It is unclear whether these arrhythmias are due to direct toxicity or secondary hypoxemia.

19. Respiratory issues
 Fatalities from acute organophosphorus agent poisoning generally result from respiratory failure due to a combination of:
depression of the CNS respiratory center
neuromuscular weakness
excessive respiratory secretions
bronchoconstriction

20. Intermediate (neurologic) syndrome
10- 40% of patients poisoned with OP develop a distinct neurologic disorder 24 to 96 hours after exposure.
consists of characteristic neurological findings including
neck flexion weakness
decreased deep tendon reflexes
cranial nerve abnormalities
proximal muscle weakness, and
respiratory insufficiency
Risk factors for the development of intermediate syndrome appear to include exposure to a highly fat-soluble organophosphorus agent, and may be related to inadequate doses of oximes
The intermediate syndrome has rarely been described following carbamate poisoning.

21. Delayed neurotoxicity
 OP induced delayed neuropathy (OPIDN) typically occurs 1-3weeks after ingestion of one of a small number of specific OP agents
Typically, the spinal cord tracts & distal axons of the lower extremities are involved more than the upper extremities.
Primary axonopathy is accompanied by secondary demyelination.
Sensory and motor fibers are involved.
This toxicity is not a result of acetylcholinesterase inhibition due to inhibition of the enzyme “neuropathy target esterase”
Affected patients present with transient, painful "stocking-glove" paresthesias followed by a symmetrical motor polyneuropathy characterized by flaccid weakness of the lower extremities, which ascends to involve the upper extremities.
The risk of developing OPIDN is independent of the severity of acute cholinergic toxicity
Survivors of acute organophosphorus agent poisoning may have neurobehavioral deficits such as decreased memory, abstraction, and Parkinsonism, which may be permanent
Delayed neurotoxicity

22. Cholinesterase Levels: Plasma cholinesterase (pseudocholinesterase) & RBC cholinesterase levels
Laboratory evidence of OP poisoning may be obtained by measuring decreases in:
Plasma pseudocholinesterase (PChE) and
RBC acetylcholinesterase (RChE) activities
Significant depression of enzyme activity may occur but still fall within the “normal” range.
It is most helpful if the patient had a pre-exposure baseline measurement for comparison (eg, as part of a workplace health surveillance program).

23. RChE activity provides a more reliable measure of the toxic effect
RBC Cholinesterse
Plasma Cholinesterase
RChE activity provides a more reliable measure of the toxic effect
25% or greater depression in activity from baseline generally indicates a true exposure effect.
RChE may recover after several months
PChE activity is a sensitive indicator of exposure but not specific as RChE activity.
PChE may be depressed due to
genetic deficiency
medical illness
chronic organophosphate exposure
usually recovers within weeks after exposure

24. Dr. TAHAR ABDULAZIZ MD, PhD
Carbamate poisoning produces reversible AchE inhibition, and spontaneous recovery of enzyme activity may occur within several hours, making these tests less useful.
Dr. TAHAR ABDULAZIZ MD, PhD

25. Dr. TAHAR ABDULAZIZ MD, PhD
Treatment
Airway, breathing, and circulation (ABCs):
Decontamination is an important part of the initial care. In general, the importance of decontamination depends on the route of poisoning.
Patients with dermal and inhalation exposures are more likely to cause nosocomial poisoning than patients with GI exposure. Patients with GI exposure should also be decontaminated.
Patients with dermal and inhalation poisonings must be decontaminated before being brought into the ED.
Case reports have described nosocomial poisoning in staff members treating patients who have been exposed to OP; one describes OP toxicity from mouth-to-mouth resuscitation.
Dr. TAHAR ABDULAZIZ MD, PhD

26. Dr. TAHAR ABDULAZIZ MD, PhD
Atropine
Atropine is a pure muscarinic antagonist that competes with ACh at the muscarinic receptor.
Atropine is most commonly given in intravenous (IV) form at the recommended dose of 2-5 mg for adults and 0.05 mg/kg for children with a minimum dose of 0.1 mg to prevent reflex bradycardia.
Atropine may be repeated every 5-10 minutes.
Severe organophosphate poisonings often require hundreds of milligrams of atropine.
Observation of 3 major signs:
dryness of mouth
flushing of face
dilatation of pupils.
Dr. TAHAR ABDULAZIZ MD, PhD

27. Dr. TAHAR ABDULAZIZ MD, PhD
Oximes {Pralidoxime (2-PAM)}: Organophosphates bind and phosphorylate one of the active sites of AChE and inhibit the functionality of this enzyme. Oximes bind to the organophosphate, causing the compound to break its bond with AChE. Most of the effects are on the peripheral nervous system because entry into the CNS is limited. The WHO protocol for oxime therapy is recommended for any patient with clinically significant poisoning.
Dr. TAHAR ABDULAZIZ MD, PhD

28. Oximes for carbamates
Decontamination, supportive care, aggressive antimuscarinic therapy, seizure control, and administration of oximes are cornerstones of management.
treatment should consist of atropine and oxime regardless of the exact toxic compound involved.
Emerg Med Clin North Am Feb;33(1):
Am J Emerg Med Nov;27(9):

29. Home Insecticides
Pyrethroids are the least toxic but should be used with cautions
A study in 2015 showed that they affect mental activities in children below 6 years and born children to mothers exposed to this substance.
Environment International
Volume 82 , September 2015, Pages 69–75
Prohibited home insecticides are those containing DIAZINON which is an OP
Prohibited in USA since 2003
& in Canada 2016

30. Pyrethroids
Pyrethroids are insecticides that are synthetic modifications of natural pyrethrins, which are extracts from the flowers of some Chrysanthemum species.

31. Mechanism of action Pyrethroids are ion channel toxins
They delay the closure of voltage-sensitive sodium channels & to prolong neuronal excitation (action potential).
They have high selective toxicity to insects in comparison to mammals.

32. Modes of Exposure Occupational exposure
Household/indoor exposure : The risk of toxicity is low when pyrethroids are sprayed indoors, e.g. in the home or office, by professional applicators.
The use of permethrin as a topical treatment or shampoo for head lice or scabies is associated with relatively low risk of toxicity

33. Clinical Manifestations of Toxicity
Mild
Moderate
Severe
Paresthaesia
Nausea
Headache
Vomiting
Dizziness
Fatigue
Anorexia
CNS depression
Increased salivation
Fasciculations
Fever
Diaphoresis
Blurred vision
Seizures
Coma
Pulmonary oedema
Respiratory failure

34. Dr. TAHAR ABDULAZIZ MD, PhD
PARAQUAT TOXICITY
Non-selective, water soluble herbicide (weed killer).
It is used since 1962.
It is available as an aqueous concentrate and in granular formulations
In Libya there are 2 compounds:
Gramaxone (yellowish liquid)
Weedol (granulation form)
Dr. TAHAR ABDULAZIZ MD, PhD

35. Dr. TAHAR ABDULAZIZ MD, PhD
Pathophysiology
Paraquat is very toxic when ingested. The exact mechanisms of toxicity is not fully understood.
The lethal dose is 1-4 grams.
Lungs are the main target of paraquat due to active, energy-dependent uptake by alveolar type I and II cells.
Skin absorption is poor. Inhalation is a possible route of toxicity
Dr. TAHAR ABDULAZIZ MD, PhD

36. Ingestion is the most common route of toxicity:
Mild: ingestion of less than 20 mg/Kg body weight.
Moderate to severe: ingestion of mg/Kg.
Very severe: ingestion of more than 40 mg/Kg.
Dr. TAHAR ABDULAZIZ MD, PhD

37. Dr. TAHAR ABDULAZIZ MD, PhD
Mechanism of toxicity
Paraquat may cause lesions in the lung by a mechanism known as redox cycling. These compounds are reduced by cytochrome P450 reductase forming a free radical.
Free radical with tissue macromolecules, one molecule of oxygen is reduced to superoxide that can then be converted to other toxic oxygen species.
These reactive compounds may cause peroxidation of cellular membranes.
The specific toxicity of paraquat to the lung results from the uptake of this compound by lung due to high pulmonary oxygen tension.
Dr. TAHAR ABDULAZIZ MD, PhD

38. Formatio of superoxide radical by PQ
Dr. TAHAR ABDULAZIZ MD, PhD

39. Dr. TAHAR ABDULAZIZ MD, PhD
Toxicity may occur through oxidation/reduction cycle producing peroxides and free radicals.
Free radicals are chemical elements that may be positively or negatively charged or neutral but possess a single unpaired electron
Dr. TAHAR ABDULAZIZ MD, PhD

40. Clinical Manifestations
Phase 1: (GIT phase): may start immediately till 72 hours; intense pain in mouth, pharynx, and stomach due to the corrosive effect of paraquat. There may be bloody vomiting or diarrhea.
Phase 2: (systemic; renal or hepatic phase): severity depends on the dose of paraquat, where manifestations of renal and or hepatic failure appear.
Phase 3: (respiratory phase): in which signs of respiratory illness appear such as cough or cyanosis
Dr. TAHAR ABDULAZIZ MD, PhD

41. Dr. TAHAR ABDULAZIZ MD, PhD
Management
There is no specific treatment; supportive therapy is important.
Gastric lavage with AC
Gastric lavage with aqueous suspension of clay (Fuller Earth or Bentonite clay).
To avoid excessive oxygen administration as this may aggravate lipid peroxidation reactions in the lungs. Significant hypoxemia to be treated with supplemental oxygen; only the lowest oxygen concentration necessary to achieve a pO2 of about 60 mm.
Charcoal hemoperfusion
Hemodialysis and forced diuresis are not effective
Dr. TAHAR ABDULAZIZ MD, PhD