2. PESTICIDES
• Single or mixture of substances
• Used from ancient to modern times
• Arsenic – herbicide, fumigant
• Copper-fungicide, utensils
• Nicotine – insecticide
• Gerhard Schrader- Father of organophophorous insecticide
• Toxicity – mostly non-target species
• Dermal, inhalation and oral route
3. Regulatory
• EPA
• Federal Insecticide, Fungicide and Rodenticide Act – Pesticides for use
• Federal Food, Drug and Cosmetic Act – allowable residues in human and
animal food
4. Insecticides
• All neurotoxicants
• Nontarget species
• Organophosphorous
• Carbamates
• Pyrethroids
• Organochlorine
• Other and Old New
Insecticides
• Rotenoids
• Nicotine
• Neonicotinoids
• Formamidines
• Avermectins
• Phenylpyrozoles
• Diamides
• Bacillus Thuringiensis
• Insect Repellents
• DEET
• Picaridin
5. Organophosphorous Compounds
• Phosphorous double bonded to oxygen (P=S, phosphorothio)
• Sensitive to hydrolysis
• Target esterases & Glutathione S-transferases
• A –esterases (paraoxanase)
• B-esterases (butylcholine)
• Acetyl choline esterase (Hallmark of OP toxicity)
• Toxicity of ACE inhibition
• Overstimulation of cholinergenic receptors (Symptoms, increased sweating, saliva,
brochonconstriction, secretion, miosis, increased gastronintestional motility, diarrhea,
tremors, muscular twitching, and various central nervous system)
• Reactivation slow depends on dimethoxy>diethoxy>>diisopropoxy
6. Organophosphorous Toxicity
• Treatment
• Atropine – dosage important
• Oxime (2-PAM) – none or harmful effect
• Diazepam to reduce anxiety
• Aging is a factor
• Biochemical measurements
• RBC AChE and Plasma BuChE
• P-nitrophenol in urine for parathion or methyl parathion
• 3,5,6 trichloropyridinol –chlorpyrifos or methyl chlorpyrifos
• DMP, DEP, DMTP and DETP
• Toxicity
• Intermediate Syndrome – weakness in muscles
• Organophosphate induced delayed polyneuropathy
• Tingling of hands and feet, progressive muscle weekness, sensory loss, distal sensory motor axonopathy
• Classic example – Ginger Jake Paralysis. Tri-ortho-cresyl phosphate (TOCP)
• Caused by NEUROPATHY TARGET ESTERASE
• Depending on Aging, treatment can promote or prevent the damage
Long term – Developmental toxicity in Children
7. Carbamates
• Derive from carbamic acid
• Carbaryl – low tox and Aldicarb – high tox
• Inhibit AceE and ButE, rapidly reversible
• Symptoms, miosis, urination, diarrhea, salivation, muscle fasciculation
• Direct inhibitors of AceE, do not require bioactivation
• Atropine treatment
• Oximes – aggravate the toxicity
• Somecase peripheral neuropathy
• Aging do not require
• Before OP toxicity –carbamate protection
• After OP toxicity - promotion
8. Pyrethroids
• Extracts of chrisanthenum cinerariaefolium
• Natural one decomposes under light
• Acid moiety, ester bond and alcohol moiety
• Modify voltage gated sodium channels
• Exits in cis and trans form; cis more toxic than trans
• Eg: LD50 trans-resmethirin 8000mg/kg cis 100 mg/kg
• Type I and Type II ( Cyano group)
• Biotransformation
• Hydrolysis of ester – CarE (heptatic and plasma)
• Oxidation of alcohol moiety – CytP450
• Type II less sensitive to hydrolysis because of cyano group
• Type II- bioactivation by CyP450
• Piperonyl butoxide used as synergist; (inhibits CyP450)
9. Type II Pyrethroid
• Behavioral arousal, aggressive
sparing and tremor
• T-Syndrome
• Disruption of voltage gated
sodium channel
• Slow the activation( opening)
• Stable hyperexcitable state
Type I Pyrethroid
• Clonic Seizures and choreoathetosis
• CS- Syndrome
• Presence of cyano group
• Prolongs channel opening
• Eventually depolarization
• GABA gated chloride channels (ivermectin
and phenobarbital prevents)
• Calcium ATPase and Ca channels, stimulate
PKC
• Deltamethrin impregnated beds do not pose
problems in children
• Occupational paresthesia (tingling)
• Topical Vit E
• Toxic to fish but not birds
10. Organochlorine Compounds
• DDT and analogs, cyclodienes and hexachlorocyclohexanes
• World over, malaria control
• Acute – neurotoxic (moderate than OP)
• Chronic – Liver and reproductive system
• Isomers (p,p’-DDT strongest)
• Stored in adipose; slow biotransformation; excreted in bile, urine and milk
• Acute effects - motor unrest, spontaneous muscle movement, abnormal susceptible to fear and other
stimuli. fine and course tremors and tonic-clonic convulsions
• Hyperesthesia and paresthesia
• Mechanism: Sodium channel, Na+ K+ and Ca+ ATPase
• Phenytoin and calcium gluconate – in animals
• Diazepam and phenobarbital –in humans
• Potent inducer of P450cyp2b and CYP3A.
• Hepatocarcinogenic in mice and rats; lung tumors and adenoma
• Possible human carcinogen
• Current alternative dimethoxy pp DDT – Similar effects
• Picrotoxin toxin binding site
11. Hexachlorocyclohexanes and
Cyclodienes
• Neurotoxic
• Lindane –gamma isomer of BHC
• Banned Agri but in shampoo
• Convulsions
• GABA chloride channel
• Phenobarbital and diazepam
Mirex and chlordecone
• Fire ants and leaf eating insects
• Hopewell, VA incident
• Tremors
• Inhibition of Na, K and Mg
ATPases and catecholamine
intake
• Cholestryamine
12. Rotenoids
• East Asian Derris Plant
• High content rotenone
• Toxic to fish; fish capture
• Blocks NADH-ubiquinone reductase
or complex 1
• Increase cardiac rates and
respiration depression
• Role in Parkinson Disease Models
• Protein inclusions and lewy bodies
– rotenone model of PD
Nicotine
• Alkaloid in tobacco plants
• Activates NAChreceptors
• Nausea, vomiting, muscle
weakness and green tobacco
sickness
13. Neonicotinoids
• Nitromethylene, nitroimine and
cyanoimine
• Targeted towards insect
NAChReceptors
Formamidines
• Structural similar to
norepinephrine
• Activates Octopamine dependent
adenylate cyclase
• (OctP receptors same as
adrengenic receptors)
• Probable human carcinogen
• Bradycardia and hypotension
• Yohimbine and adrenoceptor
antagonists
14. Avermectins
• Fungal product
• Macrocyclic lactones
• Veterinary (antihelminitic and
antiparistic)
• Humans (intestinal worms, river
blindness and lymphatic
filariasis)
• Activate GABA chloride
• Interact with -PGlycoprotein
Phenylpyrazole
• Block GABA-Cl
• Glutamate-activated chloride
15. Diamides
• Activation of Ryanodine
receptors (Ca Receptors)
• Muscle contraction
Bacillus Thuringiensis
• Soil microorganism – produce
insecticidal protein
• Bt spores contain crystals of Cry
and Cyt proteins
• Insect ingest, protein toxin in
midgut and K+influx; high PH,
osmotic lysis
16. Insect Repellants
DEET
• Biotransform CYP450 and excreted
in urine/ No strong evidence
• Lesions in male rats (alpha-2-
globulin)
• Similar to nikethamide (convulsant)
• Inconclusive BBB transport
• Recommended
• Children: 10% Adults 30%
Picaridin
• Biotransform hydroxylation and
glucuronidation, and excreted in
urine
• Olfactory receptors
