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Definition of a Pesticide
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Definition of a Pesticide

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  1. Definition of a Pesticide • Any substance intended for preventing, destroying, repelling, or mitigating any pest • Insecticides • Herbicides • Fungicides

  2. Pesticides are Not New • Fumigants • Sulfur (1000 BC) • Bordeaux mixture (CuSO4, lime (Ca(OH)2, H2O)- 1882) • Insecticides • Arsenic (16th Century) • Tobacco leaves (Nicotiana tabacum - 1690) • Rotenone (Derris eliptica – 1800s) • Pyrethrum (Chrysanthemum cinerriafolum- 1800s) • Paris Green (copper arsenite 1800s) • Rodenticides • Nux vomica (Strychnos nux-vomica)

  3. There is No Such Thing as a Completely SAFE Pesticide • But Pesticides can be USED safely. • All Pesticides have some type of biological activity • The trick is to balance efficacy and safety.

  4. Pesticide Regulations • Wiley or Sherman Act (1906) • Federal Food, Drug, and Cosmetic Act (1938) • Pesticide tolerances set in 1954 and 1958 • 1958: Delaney Act • No additive is deemed safe if found to cause cancer • Pesticides were one type of additive • Federal Insecticide, Fungicide, and Rodenticide Act • 1947 (initially administered by USDA) • 1972 (switch to EPA) • Defines registration and labeling requirements • Can cancel registration • Set tolerances • FDA monitors residue levels • Food Quality Protection Act • 1996 • Special considerations for children • Higher susceptibility • Consider child consumption patterns

  5. Development of a New Pesticide is a Lengthy and Costly Process • FIFRA • Product and residue chemistry • Environmental fate • Toxicology • Acute toxicity • Oral, dermal, inhalation, irritation, ocular, delayed neurotox, dermal sensitization • Subchronic • Rat, mouse, dog (dermal, inhalation, neurotox) • Chronic • Rodent, dog, carcinogenicity • Reproductive • Fertility, teratology, in vitro mutagenicity • Biotransformation • Occupational exposure • Spray drift • Environmental impact on non-target species • Efficacy Costs: $30 to 80M (full development and testing of a new pesticide may take 10 years)

  6. The Majority of Insecticides are Neurotoxic

  7. Toxicological Syndromes Associated with Insecticides • Acute syndromes • Cholinesterase inhibitors • Arsenic • Pyrethrins and pyrethroids • Chronic toxicosis • Delayed neuropathy (OPIDN) • Residues • Organochlorine insecticides • DDT • Wild-life problem

  8. Anticholinesterase Insecticides Organophosphorus Insecticides Carbamate Insecticides

  9. Acetylcholinesterase Inhibitors • Organophosphates (OP) • Phosphoric acid derivatives • 30 in use • First synthesized in 1937 (Bayer) • Tetraethyl pyrophosphate (TEPP) • Chemical warfare agents • Tabun (GA) • Sarin (GB) – Japanese subway attacks • Soman (GD) • VX • CMPF (GF) • Parathion (O,O-diethyl Op-nitrophenyl phosphate) • Replaced DDT in 1950s • Number of acute poisoning cases resulted • Chlorpyrifos Parathion

  10. Acetylcholinesterase Inhibitors • Carbamates • Carbamic acid derivatives • ~25 in use • Originally developed as fungicides (1930s) • Carbaryl • Physostigmine (alkaloid from Calabar bean)

  11. Interference With Neurotransmitter (Acetylcholine) Function • Acetylcholine • Synthesized in neuron cell body • Release triggered by an action potential • Sudden influx Ca2+ ---> ACh release • Broken down by acetylcholinesterase • Primary neurotransmitter in PNS • Smooth and skeletal muscle • CNS (distributed throughout) • In the developing brain, every neuron expresses cholinesterase activity even if it isn’t cholinergic in adulthood.

  12. Mode of Action Cholinergic neuron Acetylcholine Effector organs: Smooth muscle Skeletal muscle CNS

  13. Mode of Action • Acetylcholinesterase inhibitors • Carbamates • Carbamylation of enzyme occurs • Reversible • Organophosphates • Enzyme phosphorylation occurs • “Aging” • Irreversible • Aging occurs over a 12-24 hr time period

  14. C Op Carbamate Organophosphate Mode of Action Treatment: Atropine 2-PAM Choline + Acetylcholine Acetate Acetycholinesterase inhibitors Acetylcholinesterase Synaptic cleft Muscarinic Nicotinic

  15. Clinical Signs • Clinical signs related to excessive stimulation of nicotinic and muscarinic receptors • Muscle tremors • CNS effects • Respiratory paralysis (this is what causes death) • Salivation, Lacrimation, Urination, and Defecation • CNS signs • Bronchospasm • Bronchial secretions • Miosis • Bradycardia

  16. Organophosphate Insecticides • Toxicology • Delayed effects (OPIDN) • Ginger Jake paralysis • Tri-o-tolyl phosphate (TOTP) • Leptophos, mipafox, chlorpyrifos, DFP • All organophosphates are required to be tested for their ability to produce OPIDN before they are marketed (Hen test)

  17. OPIDN • Organophosphate Induced Delayed Neuropathy • Clinical signs • Ataxia and paralysis • Develop 10 to 14 days after exposure • Neuropathology • Wallerian-type degeneration • Mode of Action • Inhibition of neurotoxic esterase (NTE) is generally predictive

  18. As Animals Mature, They Become Less Sensitive to Chlorpyrifos Toxicity (Moser et al, Toxicol. Sci, 1998)

  19. Generic OP Pathway Oxon Parent Pesticide Hepatic Activation Bind to CaEs Hydroylzed by A-Esterases Inhibit AChE

  20. Acetylcholinesterase in the Young Brain is NOT more Sensitive to Organophosphorus Pesticide Inhibition Mortensen et al., Toxicol. 1998

  21. Developmental Profiles of Carboxylesterase and A-Esterase in Rats (Mortensen et al., J. Biochem. Toxicol. 1996; Moser et al, Toxicol. Sci, 1998)

  22. Generic OP PathwayAdult vs Young Rat Oxon Hepatic Activation and probably Deactivation Parent Pesticide Bind to CaEs Hydroylzed by A-Esterases Inhibit AChE

  23. Developmental Profiles of A-Esterase in Humans A B Arylestease (U/mL) Arylesterase (U/mL) Age (months) Age (months) C Arylesterase (U/mL) Age (months) Cole et al, 2003

  24. Pyrethrin and Pyrethroid Insecticides

  25. Pyrethrin and Pyrethroid Insecticides • Pyrethrins • Naturally derived insecticide • Chrysathemum • Natural pyrethrins include pyrethrin I, pyrethrin II, jasmolin I, jasmolin II, cinerin I and cinerin II.3 • Pyrethroids • Synthetic insecticides • Slightly more persistent • Fenvalerate • Deltamethrin

  26. Pyrethroids • Natural pyrethrins are light sensitive and undergo rapid photodegradation • Pyrethroids that contain a cyano substituent at the alpha-carbon of the phenoxy-benzyl moiety have been classified as type II; pyrethroids which lack this alpha cyano moiety as type I • Type I (T syndrome): Tremors, tachypnea, "running fits," hyperthermia, and salivation within 1-2 hours of injection • Allethrin • Pyrethrin I • Resmethrin • Tetramethrin • Type II (CS syndrome): Whole body tremors, hypersensitivity, occasional running fits, choreoathetosis (sinuous writhing), hypothermia, and generalized seizures • Cypermethrin • Deltamethrin • Fenvalerate

  27. Pyrethrin and Pyrethroid Insecticides • Toxicity • Low oral toxicity • LD50 quite variable • 25 to 10000 mg/kg • Rapid hydrolysis in the gastrointestinal tract • Liver metabolism • Synergists • Microsomal enzyme inhibitors • Piperonyl butoxide

  28. Interference with voltage gated sodium channels. Type I keep channels open for shorter period vs. Type II Enhanced sodium ion conductance Mode of Action (Overstimulation of the Nervous System)

  29. Clinical Signs • Muscle tremors • Mixed CNS effects • CNS depression • CNS excitation • Seizures • Increased salivation • Vomiting • Ataxia • Hypo and hyperthermia • Paresthesia

  30. Generic Pyrethroid Pathway Pyrethroid Keep Na Channels Open Hydrolyzed by P450s Hydroylzed by CAEs

  31. 3.5 3.5 Weanling, 4 mg/kg DLT Adult, 30 mg/kg DLT Choreoathetosis 3.0 3.0 2.5 2.5 2.0 2.0 1.5 1.5 1.0 1.0 Salivation Score 0.5 0.5 Choreoathetosis Score 0.0 0.0 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400 Time After Dosing (minutes) Time After Dosing (minutes) Weanling, 4 mg/kg DLT Adult, 30 mg/kg DLT Salivation

  32. Newer Pesticides: • “Mectins” (Nicotinic receptor agonists, specific for non-mammalian receptors) • Avermectin • Ivermectin • Anthelmentic, insecticide • Management of river blindness (Onchocerca) • Low dermal absorption • Minimal biotransformation

  33. Final Thoughts • Most of what has been presented relates to acute toxicology. • What about long term effects of low level exposure to pesticides? • What about effects on the developing nervous system?