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
17. Herbicides
• Capable of killing or injuring the plants
• Types of herbicides
• Preplanting
• Preemergent
• Postemergent
• Contact
• Translocated
• Relatively Low Acute toxicity except paraquat (contact dermatitis)
• Five major class
• Chlorophenoxy
• Bipyridyl
• Chloroacetanilides
• Triazines
• Phosphomethyl amino acids
18. Chlorophenoxy Compounds
• 2,4-D; 2,4,5 T; and MCPA (different forms of phenoxy acetic acids)
• Mimics plant hormone auxin
• Produce uncontrollable growth in target plants
• Contaminations, TCDD, PCDD
• 50: 50 mixture of 2,4-D; 2,4,5 T – Agent Orange (Vietnam War)
• Low to acute toxicity; Dogs are more sensitive
• Becomes acidic –vomit, moth burning, hypotension, coma
• Alkalization of urine and intraven bicarbonate administration
• Possible mechanism 1) cell damage 2) Ac-CoA disturbance 3)uncoupling oxidative
phosphorylation
• Possible Demyleination and degeneration of CNS
• Associated with non-Hodgkin lymphoma and soft tissue sarcoma/ no strong evidence
• Classified as Group D agent (non classifiable as human carcinogen)
19. Bipyridyl Compounds
• Paraquat (most concern)
• Skin sensitizer
• Accumulates in lung and kidney
• High concentration in type II and I /Clara cells
• Toxicity: Redox cycling; superoxide generation and
lipid peroxidation
• Stages of lung destruction; destructive phase;
proliferative phase and intensive fibrosis
• Dexamethasone with PG induction and sodium
salicylate in animals
• Blue stentching pigment added
• Etilogical in Parkinson Disease [Structure similar to
MPP+ and MPTP- Similar to rotenone]
• Some evidence for neurodegeneration to
dopaminergic neurons [dose level not concern to
humans]
DiQuat
No Skin sensitizer; no lung accumulation
Kidneys and eyes- free radical mechanism
Ocular toxicity
20. Chloroacetanilides
• Alachlor, Acetochlor, metolachlor and butachlor
• Inhibit synthesis of lipids, alcohols, fatty acids and terpenoids
• Alachlor – ocular toxicity in Long-Evan Rats – progressive uveal degeneration
syndrome
• Not observed in mice, dogs or any other rats.
• Produce tumors
• Basis of weight of evidence – non genotoxic
• Probable human carcinogens ( Group B2)
• May be species specific
• Forms quinone metabolites – radical producers, glutathione scavenger
• Current Recommendation for alachlor- likely at high doses but not likely at low
doses
21. Triazines
• Atrazine, simazine, propazine
• Inhibition of photosynthesis
• Possible clastogenic of atrazine-
• Mammary carcinomas in Sprague-dawley rats
• Possible endocrine disruption
• Atrazine and Simazine (Group 3 by IARC; not classficable to humans)
• Atrazine – possible feminization of frogs- endrocine disruption; EPA
revisiting
22. Phosphonomethyl amino acids
Glyphosphate
• Inhbition of 5-enol
pyruvylshikimate- 3-phosphate
• Present only in plants
• Group E by EPA( non carcinogen
to humans)
• Surfactant POEA –possible
damage
Glufosinate
• Inhibit glutamine synthetase
• Increase ammonia and
glutamine deficiency
• dosage at this level not concern
to humans
• Role of surfactants in toxicity
23. Fungicides
• Low acute toxicity to mammals
• Oncogenic risk
• Banned
• Methylmercury – Iraq- grains
• HCB – Turkey- black sore, blistering skin, hepatomegaly and
immunosupression
24. Captan and Folpet
• Contains, chlorine, carbon and sulfur
• Thiophosgene, a common metabolite
• Duodenal tumors in mice
• Probable human carcinogens (Category B2) and recently changed to “not
likely to be a human carcinogen when used according to label directions”
• Resembles thalidoamide
25. Dithiocarbamates
• Maneb (Mn); Ziram and Zineb (Zn); and mancozeb (Mn and Zn)
• Thiram without any metal moiety
• Ethylenethiourea (ETU) common metabolite
• Thyroid tumors – inhibition of T4 and T3- thyroid hypertrophy
• Liver tumors in mice; developmental and teratogenicity in rats
• Hind limb paralysis (Carbondisulfide – Ethylene bisthiocyanate-sulfide EBIS)
Maneb – associated with Parkinson
Maneb with paraquat –potentiation –MPTP –dopaminergic
DTC resembles disulfuram – known to increase acetaldehyde levels
26. Chlorothalonil
• Highly toxic in intraperitoneal and inhalation route
• Eye lesions in rabbit and dermal irritation
Benzimidazoles
• Inhibit microtubule assembly – chromosomal aberrations
• Contact dermatitis
• Liver, testes, bone marrow and gastrointestional tract
• Affect male reproductive system in animals
27. Inorganic and organometal
• Copper Sulfate
• Bordeaux mixture (copper sulfate and calcium hydroxide)
• Tributyltin
• Antifouling agent
• Adverse effect to oyster –banned in 2008
• Triphenyltin
• Reproductive toxicity and endocrine disruption
Organic mercury removed
29. Fluoroacetic acid
• Alias (Compound 1080 or Sodium Fluoroacetate)
• Inhibits krebs cycle and aconitase (Fluorocitrate)
• Potent chelator of calcium ions
• CNS (agitation, convulsion and coma) and Heart toxicity (ventricular
tachycardia, hypotension and fibrillation)
• Antidote: glycerol monoacetate (monoacetin)
• Procainamide (cardiac arrhythmia) and barbiturates (Seizure)
30. Thiourea
• ANTU
• Toxicity to lung
• Edema in subepithelial spaces of aleveolar wall
• Binds to lung macromolecules
• Human poisonings
• Chloralase and ANTU
• Impurity - B-naphthylamine – bladder cancer
31. Anticoagulants
• Spoiled sweet clover silage – hemorrhagic disorder –
bishydroxycoumarin (dicoumarol)
• Warfarin
• Inhibition of Vitamin K epoxide reductase
• Antagonize – Vitamin K- prevent clotting factor synthesis (Factor, II, VII, IX
AND X)
• Rats became resistant and second generation anticoagulants
• Superwarfarins Brodifacuom and difenacoum
• Indane 1, 3-diones derivaties (dophacinone and chlorophacinone)
• Increased blood half-life
32. Norbormide
• Selective to rats
• Vasoconstrition
• Zinc Phosphide
• Phosphine gas
• Necrosis of GI and Cyto C
oxidase inhibition
• Aluminium phosphide
• GI, CV and electrolytic imbalance
Thallium Sulfate and Arsenic
alopecia (hairloss)
Strychnine
seeds of nux-vomica
Antagonize glycine (inhibitory
aminoacid)
potent convulsant
Red Squill (Sea Onion)
CV and CNS
Pyriminil –withdrawn- Complex I
INHIBITION - diabetogenic
33. Fumigants
• Methyl Bromide
• Concern for ozone depletion
• Long lasting neuropsychiatric disorders and neurotoxicity
• Acute: respiratory, GI and neurologic
• Conjugation with GSH
• Positive in several genotoxic test
• Forestomach carcinoma and pituatry adenoma
• IARC group 3 (not classificable as human carcinogen)
• Chloropicrin added for pungent smell
34. 1,3 Dichloropropene
• Irritant
• Redness and necrosis of skin
• Mercapturic acid – major metabolite
• Epichlorohydrin – stabilizing agent
35. Metam-Sodium
• MITC is the active product and CS2
• Bladder, kidney and liver
• Allergic dermatitis
• Irritant, buring of eyes, nose and throat
• Alternative of methyl bromide
36. Sulfur Compounds
• Elemental Sulfur – ancient pesticide – grapes and tomato
• Too acidic to certain crops
• Humans (dermatitis) and cerebrocortical necrosis (cattles) –H2S
• Sulfurdioxide (grapes)
• Fumigant, antimicrobial, high water soluble and food additive
• Sulfuryl fluoride
• Structural and storage
• Neurotoxicity and microvacuolation in various brains
37. No longer in US
• CS2 – neurotoxic
• CCl4 – hepatotoxicant
• 1,2,dibromo-3-chloropropoane – male reproductive toxicant
• Ethylene dibromide – carcinogen
