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Pesticides

Pesticides. Principles of Toxicology. Pesticides. EPA definition: “substances or mixtures of substances intended for preventing, destroying, repelling or mitigating any pest…”. A bit of history…. Sulfur. Chinese - 1000BC Europe - 1800s CA - today !. Arsenic-containing Strychnine

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Pesticides

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  1. Pesticides Principles of Toxicology

  2. Pesticides • EPA definition: “substances or mixtures of substances intended for preventing, destroying, repelling or mitigating any pest…”

  3. A bit of history… • Sulfur • Chinese - 1000BC • Europe - 1800s • CA - today ! • Arsenic-containing • Strychnine • Nicotine (tobacco leaves extracts - 1690) • Pyrethrum (chrysanthemum extract) • Bordeaux mix: copper, lime (Ca(OH)2), water

  4. Later… • 1930’s - modern era chemistry • Alkylthiocyanate • Dithiocarbamate • Bromide compounds • WWII - • DDT • Dinitrocresol • 2,4 D • Since then, synthesis with goal improved specificity, reduced toxicity… • No such a thing as “safe pesticide”

  5. Integral part of crop and health protection Poisonings are anticipated… 3mil acute cases annually (ww) 220,000 deaths CA - 25,000 pesticide related illnesses, annually USA - 80,000

  6. Efficacy of crop protection

  7. Pesticide poisonings by occupational activity

  8. Medical successes • DDT • Typhus in Naples, Italy • River blindness, West Africa • Malaria - Africa, Asia, Middle East There are still many parasitic and vector-borne diseases…

  9. Regulations… • 1906 - First Federal Food and Drugs Act • 1938 - Federal Food, Drugs and Cosmetics Act • 1958 amend. - Delaney clause: “no additive shall be deemed safe if …found to induce cancer…” • 1947 - FIFRA: Federal Insecticide, Fungicide and Rodenticide Act: all pest control products under one law - by USDA • 1972 - FIFRA reorganized and passed to EPA • FIFRA Amendments - 1975, ‘78, ‘80, 84 • 1996 - Food Quality protection Act (children) • Developing countries adapt or lack regulations

  10. Nervous System Central Peripheral Afferent Efferent Autonomic Somatic Para-Sympathetic Sympathetic ENS

  11. Anatomic Classification CNS Skull and Spinal cord PNS 12 pairs of cranial nerves 31 pairs of spinal nerves afferent CNS PNS efferent

  12. Sympathetic ANS Fight or flight Parasympathetic ANS Rest and digest

  13. Parasympathetic: Cholinergic cranio-sacral Sympathetic: Adrenergic thoraco-lumbar

  14. Parasympathetic nerves 4 Cranial III oculomotor VII facial IX glossopharyngial X vagus Sacral S2 S3 S4

  15. Sympathetic nerves T1 . . . . T12 L1 L2 L3

  16. Afferent  dorsal root – then divide Efferent  ventral root Afferent Nerves Efferent Mixed Neurons Spinal nerves are mixed for major length

  17. Structure of a typical neuron

  18. Pre-ganglionic neuron organ Post-ganglionic neuron Ganglion Multi-neuron synapse Neuroeffector junction

  19. Somatic Ach Parasympathetic -cholinergic Ach Ach Sympathetic - adrenergic Ach Adr/NA

  20. Feature SympatheticParasympathetic Start point thoraco-lumbar cranio-sacral Ganglion near spine on organ (terminal) Ganglion synapse Ach Ach Pregangl. neuron short long Postgangl. neuron long short Effector synapse Adr Ach Effector organs throughout body limited

  21. Typical Synapse

  22. Cholinergic Transmission

  23. Acetylcholine Synthesis O CH3C-O-+ HO-CH2-CH2-N+(CH3)3 Acetate Choline Choline Acetylase Coenzyme A O CH3C-O-CH2-CH2-N+(CH3)3 Acetylcholine

  24. Acetylcholine Catabolism O CH3C-O-CH2-CH2-N+(CH3)3 CH3C-O- + HO-CH2-CH2-N+(CH3)3 Acetylcholine Cholinesterase O Acetate Choline

  25. Cholinergic Receptors Muscarinic: M1 CNS, sympathetic (exceptions), presynaptic M2Smooth muscle, heart, presynaptic M3 Exocrine glands, blood vessels Nicotinic: NMskeletal muscle NN ganglia (post-), presynaptic

  26. Acetylcholine Nicotinic Receptor

  27. Nicotinic Receptor structure a b d a g Ion Channel

  28. Na+ d g a a b Na+

  29. Outside Inside Muscarinic receptor Agonist G protein

  30. Muscarinic receptor G- proteins Excitatory action Inhibitory action Phosholipase C Adenylic cyclase K+ channels

  31. Muscarinic receptor stimulation - - - - Gi Signal transduction cascade involving Adenylic cyclase Protein Kinase A

  32. Muscarinic receptor stimulation Gq Signal transduction cascade involving Phospholipase C

  33. Cholinergic agonists

  34. Adrenergic Transmission

  35. Sympathetic Nerve Terminal Tyrosine 3 1 mitochondria contains MAO, oxidizes amines transport exocytosis 4 2 DA, Nepi stored with ATP in granules 5 a , b Receptors re-uptake

  36. Adr (NA) synthesis

  37. Adrenergic Receptors Alpha a a1 most effector cells a2 presynaptic, lipocytes, platelets, some smooth muscle Beta b b1 effector cells (*heart), brain, lipocytes, presynaptic b2 smooth muscle and myocardium b3 lipocytes

  38. Adrenergic receptors: a2 and b - + Adenylyl cyclase b receptor a2 receptor

  39. + Adrenergic receptors: a1 Phospholipase C a1 receptor

  40. Pesticides • Organochlorines • ChE inhibitors • Organophosphates • Carbamates • Phenoxyherbicides • Pyrethroids • Bromine-based • Phenol- derivatives • Dipyridyl derivatives

  41. Organochlorine insecticides

  42. Organochlorine insecticides • DDT • first commercially produced insecticide (1940’s) • banned in the US in the 1970’s but is still manufactured and exported (1 ton/day) • Cyclodienes • Most toxic (CNS) and persistent pesticides known • HCH and Cl-benzene • Mixtures of isomers • Medicinal use (lice shampoo) (lindane) • t1/2 = 7-30y • Bioaccumulates • Persistent • Lipophilic • Non-selective • Endocrine disrupter • Reproductive toxins • Neurotoxins (Lindane)

  43. Observed effects • DDT • Enzyme induction • Competes with estradiol for receptor • Cyclodienes • Reproductive toxicity (reduced fertility, loss of pups, teratogenic) • CNS toxicity • HCH and Cl-benzene • CNS toxicity • Increased hepatocellular tumors (mice)

  44. Mechanisms of action • DDT • Peripheral sensory neurons • prolonged negative afterpotential in neurons • K+ transport, inactivate Na+ channel closure, inhibit Na+ /K+ and Ca2+ /Mg2+ ATPases, inhibit calmodulin-transport of Ca2+ (fig. 22-4) • Cyclodienes • CNS localized • GABAA receptor/channel antagonists, inhibit Cl--uptake and Na+ /K+ and Ca2+ /Mg2+ ATPases • HCH and Cl-benzene • Suggested similar to cyclodienes but unknown

  45. Cholinesterase inhibitors • Organophosphates (OP) and Carbamates • Strong Acute neurotoxicity - AChE inhibition (cholinergic effects) • Nervous system toxins - nerve gas (sarin)

  46. 1st OP: TEPP (tetraethylpyrophosphate), followed by parathion 1st carbamic: 1930 WWII chemical warfare 1988 Iraq- against Kurds 1994 Japan 1995 Tokyo subway

  47. Cholinesterase O O + CH3 C - O - CH2 - CH2 - N(CH3)3 CH3C-O- + HO-CH2-CH2-N(CH3)3 Esteratic Anionic +

  48. X X R1-2 = e- withdrawing = aliphatic Organophosphates O R1 Parathion Malathion Soman Ecothiophate P R2

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