ADVS 5400 Section 10: Pesticides (Insecticides, Herbicides, Rodenticides)
2-PAM is ineffective against ______ AChE.
"Aged" (stable)
What is human's primary exposure to DDT?
"Prime" red meat
Because of limited supply of flowers, what are most of the Pyrethrin insecticides in use today?
"Pyrethroids" or synthetic derivatives of natural pyrethrum
What is the normal catalytic action of AChE?
1) Ach binds to both AChE binding sites 2) Inactive Choline and Acetic acid products are formed
What are the 2 binding sites found on Acetylcholinesterase (AChE)?
1) Anionic site (-) 2) Esteratic site (HG; G= Serine active center)
Lindane: Chronic toxicity (in animals)
1) Blood disorders: Leukemia 2) Hepatotoxic, Carcinogenic
What is the catalytic action of AChE when bound to Carbaryl (Carbamate- AChE inhibitor)?
1) Carbyl (Carbamate) binds to Serine active center binding site 2) α-Naphthol and Carbylated AChE (stable) formed
What are the 2 forms of Herbicides mentioned?
1) Chlorophenoxy herbicides 2) Bipyridyl herbicides
Rodenticides: Strychnine- Symptoms of poisoning
1) Intermittent, severe convulsions lasting ½-2 min in 15 min intervals 2) Opisthotonos: Violent convulsion that tear major muscle groups 3) Hypersensitive to noise/light, setting off more convulsions
DDT: Characteristics
1) Long environmental t0.5 2) Rapidly absorbed, slowly metabolized, enterohepatic cycling
Chlorinated Cyclodienes: Toxicology
1) More acutely toxic than DDT 2) CNS/PNS toxicants 3) Biotransformed to epoxides 4) Possible carcinogens
What are the 2 types of Organophosphates? Which came first?
1) Nerve Gases (1st) 2) Insecticides (developed from nerve gases)
What is the catalytic action of AChE when bound to Paraoxon (organophosphate)?
1) Paraoxon (OP) binds to Serine active center binding site 2) Paranitrophenol and phosphorylated AChE (stable) formed 3) "Aging" occurs to form extremely stable product; 2-PAM antidote is no longer effective
What are 2 examples of Bipyridyl hebicides?
1) Paraquat (one of most widely used worldwide) 2) Diquat
Chlorinated Cyclodienes: Chronic toxicity
1) Psychological disorders 2) Intermittent twitching 3) Convulsions 4) Hepatoxic, Carcinogenic
Rodenticides: Strychnine- Treatment
1) Short-acting barbiturate (hexobarbital) immediately after convulsion 2) Activated charcoal: Binds strychnine 3) Potassium permanganate (KMnO4): Oxidizes strychnine 4) Short t0.5, degraded rapidly (survival likely if alive after 2 hr)
What are 2 examples of Rodenticides?
1) Strychnine 2) Warfarin (Coumadin)
Organophosphates: Symptoms of acute exposure
1) Weakness, pale skin 2) Difficulty breathing; ↑ bronchial secretions (mucus) 3) Salivation, sweating 4) Bradycardia (↓HR) 5) Tremors, twitching 6) Miosis (constricted pupils) 7) Cyanosis, apnea 8) Convulsions, death
Organophosphates: Characteristics as a chemical class
1) Well absorbed by ALL routes (except Malathion) 2) Short t₀.₅; Rapidly degrades in environment 3) Little groundwater contamination and bioaccumulation (Advantage over DDT) 4) Requires repeated application
What are the normal effects of Acetylcholine (ACh) on the Parasympathetic nervous system (automated functions)?
1) ↑ Exocrine glands 2) ↑ GI tract smooth muscle 3) ↓ HR
What are the normal effects of Acetylcholine (ACh) on the Sympathetic Nervous System ("Fight or Flight")?
1) ↑ HR 2) ↑ Blood vessels 3) ↑ Sweat glands 4) ↓ Smooth muscle: GI tract, lungs
What Prohibition-era epidemic was caused by the insecticide Tri-O-Tolyl-Phosphate (TOTP)?
30,000-100,000 paralyzed from TOTP-contaminated or adulterated alcoholic jamaican ginger extract ("Jake"); Found in drums that had contained shellac (TOTP); Resulted in "Jake Leg"
At the neuromuscular junction, ______ is released and causes muscle fibers to twitch.
ACh
Where does the antidote for Acetylcholinesterase inhibitors act?
ACh receptor (ACh antagonist)
2-PAM (part 2 of dual therapy for organophosphate poisoning)
Accelerates dephosphorylation of AChE (enhances hydrolysis of phosphate group from AChE); Given shortly after Atropine
Chlorophenoxy herbicides
Acids; Water soluble; Absorbed well orally, but not dermally; Rapidly excreted unmetabolized (Ex. 2,4,5-T)
Bipyridyl herbicides- Toxicology
Acute toxicity: Regardless of exposure route, concentrates in lung: Specific pulmonary toxicant- lung scarring, emphysema, often fatal
DDT Toxicity targets: Acute? Chronic?
Acute: CNS Chronic: Liver (cancer, CNS, hepatotoxicity)
Chlorinated Cyclodienes toxicity targets: Acute? Chronic?
Acute: CNS Chronic: Liver, cancer
Where is DDT stored in the body?
Adipose tissue (All humans have DDT found in body)
Atropine (part 1 of dual therapy for organophosphate poisoning)
Alkaloid from plants like Atropa belladonna (deadly nightshade) and Datura stramonium (Jamestown weed); Occupies same muscarinic postsynaptic receptors of PNS as Ach (blocks receptors); Ach antagonist (reduces symptoms)
When do the symptoms of acute organophosphate exposure occur?
Almost immediately (6-7 mins post-exposure)
Insecticides: Carbamate- Treatment
Atropine only, no need for 2-PAM
Many Organophosphates require ______ before they are effective. What does this include?
Bioactivation; P450s convert from phosphorthioate (P=S) to phoshooxon (P=O) functional group
Where is the insecticide Lindane stored in the body?
Body fat
Lindane: Acute toxicity (in animals)
CNS toxicant: More violent convulsions than DDT
Insecticides: Pyrethrins- Mechanism of Action
CNS toxin: Block Ca⁺², Mg⁺² ATPases
Chlorinated Cyclodienes: Acute toxicity
CNS: 1) Dizziness, headache 2) Nausea, vomiting 3) Clonic (thrashing) and tonic (tetani) convulsions 4) Effects eventually subside due to redistribution into fat
DDT: Acute Toxicology
CNS: 1) Tremors, ataxia, seizures 2) Convulsions 3) Respiratory failure
Insecticides: Carbamate- Mechanism of Action
Carbamylation of AChE (AChE inhibitors)
What do the insecticides Carbamates include?
Carbaryl, Baygon, Temik
Insecticide: Tri-O-Tolyl-Phosphate (TOTP)- Toxicity
Causes delayed, long-term neurotoxicity; Muscle flaccidity of arms/legs causing "shuffling gait" (Jake Leg)
DDE contains less _____ than DDT.
Chlorine (less toxic)
What are the symptoms of acute organophosphate exposure consistent with?
Consistent with excess ACh
How does Methoxychlor differ from DDT structurally?
Contains methoxy groups instead of chlorines (Slightly lower Kow)
What is the principal metabolite of DDT in the body? How does it compare to DDT?
DDE; Less toxic (yet still toxic); Very Lipophilic
Insecticide: Dicofol (Kelthane)
DDT alternative (trace DDT contamination); Only Acaricide: Kills Acari, spider mites, on fruit, vegetables, tree nuts, ornamentals, hops, cotton
Insecticide: Methoxychlor
DDT replacement; Degrades rapidly in environment; Rapidly metabolized (short t0.5)
How long is the recovery from organophosphate poisoning?
Days or weeks, depending on severity
Bipyridyl herbicides- Uses
Defoliant for cotton (banned in many countries); Marijuana eradication; Pasture renovation, weed control
Insecticides: Pyrethrins
Derived from flowers of Chrysanthemum cinerariaefolium and coccineum; Mixture of six compounds termed "pyrethrins" or "pyrethrum;" Flowers imported from Kenya, Rwanda, Tanzania, Ecuador
Insecticides: Carbamate- Toxicology
Direct-acting: Do NOT require metabolism; Carbamylated AChE spontaneously hydrolyzes
What is the treatment of Organophosphate Poisoning?
Dual antidote therapy: 1) Antropine Sulfate 2) 2-PAM
Insecticides: Chlorinated Cyclodienes (examples)
Endrin, Aldrin, Dieldrin, Chlordane, Toxaphene; All banned except Chlordane for fire ant control in power substations
The botanical insecticide Pyrethrins have been found to be ______.
Estrogenic
Insecticides: DDT (chlorinated aromatic)
First "miracle" pesticide; Aedes aegypti principal target; IARC Class 2B carcinogen (possible)
Bipyridyl herbicides have a _____ hazard rating.
High
Bipyridyl herbicides
Highly polar (charged- transported via transport proteins); Poorly absorbed through skin/GI; Paraquat used in murders/suicides
Organophosphates: Toxicology
Inhibits acetylcholinesterase (AChE- degrades acetylcholine); Acetylcholine then accumulates at receptors in CNS and PNS
Dicofol is not effective against ______.
Insects (besides Acari, spider mites)
Organophosphates: Mechanism of Toxicity
Irreversible covalent phosphorylation of the serine active site of the acetylcholinesterase (AChE) enzyme
Insecticide: Malathion
Less hazardous than OPs; Acute toxicity less than parathion (OP); Widely used; Phosphate-enzyme ester rapidly hydrolyzed
DDT: Chronic Toxicology
Liver: 1) Synergizes other hepato-toxicants 2) Liver damage/cancer 3) Endocrine disruption
Dicofol has a _____ acute toxicity against mammals.
Low
How does the amount of biomagnification of Methoxychlor relate to DDT?
Methoxychlor biomagnifies less than DDT
Human poisonings by Warfarin (Coumadin) are rare with dosing(s) being required.
Multiple
Where are the Acetylcholinesterase enzymes found at the neuromuscular junction?
Muscle
Rodenticides: Strychnine
Natural alkaloid (plant chemical containing N) from Strychnos nux-vomica plant; Most violent poison known (can kill large man)
Acetylcholinesterase inhibitors are utilized in both ______ and ______.
Nerve agents; Organophosphate insecticides
What is the main difference between organophosphate nerve gases and insecticides?
Nerve gases do NOT require metabolism, while insecticides DO require bioactivation by P450s first (P=S to P=O)
Chlorophenoxy herbicides- Toxicology
Nervous system effects; 2,4,5-T toxicology from contamination of TCDD; 2,4,5-T one of 3 components of "Agent Orange"
Insecticide: Lindane (misnamed benzenehexachloride or "BHC")
Not well absorbed through skin; Carcinogen
Atropine, part of dual therapy for organophosphate poisoning, is extremely toxic. What symptoms can it cause?
Opposite symptoms to Oranophosphates (Acetylcholinesterase inhibitors) 1) ↑HR (pink cheeks) 2) Dilated pupils 3) Dry mouth
What is a biomarker of organophosphate poisoning?
Paranitrophenol
Of the Bipyridyl herbicides, which is more toxic?
Paraquat>Diquat
Organophosphates: Insecticides Examples
Parathion, Malathion, Diazinon
What are the restricted uses of the insecticide Lindane?
Pet collars, dog shampoos, non-food animals, home ornamentals, wood treatment, lice control in people
What is a biomarker for Organophosphate exposure?
Plasma cholinesterase
Insecticide: Tri-O-Tolyl-Phosphate (TOTP)- Sources
Plasticizer used in lacquer, shellac products
What is an example of a botanical (naturally plant-produced) insecticide?
Pyrethrins
What is the major insecticide currently in use? Why?
Pyrethrins; Much less toxic than others (especially OPs)
Organophosphates: Nerve Gases
Pyrophosphates; Developed in 1940s in Germany; NO metabolism required; Extremely acutely toxic
Soil residues of Dicofol decrease ______, but traces remain for more than 1 year.
Rapidly
Insecticides: Carbamates
Related to OPs in mechanism of action (AChE inhibitors); Lower dermal toxicity/hazard than OPs
Organophosphates: Insecticides
Require bioactivation by P450s
Why have some insects become immune to DDT?
Resistance due to different enzymes (P450s, Phase II)
Organophosphates: Nerve Gases Examples
Sarin, VX, Tabun
What alkaloid related to Atropine is used for motion sickness?
Scopolamine
How do the symptoms of Methoxychlor relate to DDT?
Similar acute symptoms to DDT
Insecticides: Carbamate- Symptoms
Similar to OPs, but shorter-lived
What are the normal effects of Acetylcholine (ACh) on the Central or Somatic Nervous System (Brain, Spinal cord)?
Skeletal muscle control
Warfarin (Coumadin) has been found to be a natural contaminant of what plant? By what research group?
Sweet clover; Wisconsin Alumni Research Fund (WARFarin)
Where are Acetylcholinesterases found in the body? Why?
Synaptic junctions; Ach is released into synaptic cleft to post-synapse or muscle to propagate signal; Acetylcholinesterases degrade Ach thereby controlling signal
Organophosphate nerve gases are much more potent than insecticides. (TRUE/FALSE)
True
Rodenticide: Warfarin (Coumadin)
Vitamin K antagonist: Anticoagulant, inducing internal hemorrhaging; Acts 8-12 hrs after ingestion; Dispersed in grain-based baits
