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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 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 • Nicotine (tobacco leaves extracts - 1690) • Pyrethrum (chrysanthemum extract) • Bordeaux mix: copper, lime (Ca(OH)2), water
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”
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
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…
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
Nervous System Central Peripheral Afferent Efferent Autonomic Somatic Para-Sympathetic Sympathetic ENS
Anatomic Classification CNS Skull and Spinal cord PNS 12 pairs of cranial nerves 31 pairs of spinal nerves afferent CNS PNS efferent
Sympathetic ANS Fight or flight Parasympathetic ANS Rest and digest
Parasympathetic: Cholinergic cranio-sacral Sympathetic: Adrenergic thoraco-lumbar
Parasympathetic nerves 4 Cranial III oculomotor VII facial IX glossopharyngial X vagus Sacral S2 S3 S4
Sympathetic nerves T1 . . . . T12 L1 L2 L3
Afferent dorsal root – then divide Efferent ventral root Afferent Nerves Efferent Mixed Neurons Spinal nerves are mixed for major length
Pre-ganglionic neuron organ Post-ganglionic neuron Ganglion Multi-neuron synapse Neuroeffector junction
Somatic Ach Parasympathetic -cholinergic Ach Ach Sympathetic - adrenergic Ach Adr/NA
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
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
Acetylcholine Catabolism O CH3C-O-CH2-CH2-N+(CH3)3 CH3C-O- + HO-CH2-CH2-N+(CH3)3 Acetylcholine Cholinesterase O Acetate Choline
Cholinergic Receptors Muscarinic: M1 CNS, sympathetic (exceptions), presynaptic M2Smooth muscle, heart, presynaptic M3 Exocrine glands, blood vessels Nicotinic: NMskeletal muscle NN ganglia (post-), presynaptic
Nicotinic Receptor structure a b d a g Ion Channel
Na+ d g a a b Na+
Outside Inside Muscarinic receptor Agonist G protein
Muscarinic receptor G- proteins Excitatory action Inhibitory action Phosholipase C Adenylic cyclase K+ channels
Muscarinic receptor stimulation - - - - Gi Signal transduction cascade involving Adenylic cyclase Protein Kinase A
Muscarinic receptor stimulation Gq Signal transduction cascade involving Phospholipase C
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
Adr (NA) synthesis
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
Adrenergic receptors: a2 and b - + Adenylyl cyclase b receptor a2 receptor
+ Adrenergic receptors: a1 Phospholipase C a1 receptor
Pesticides • Organochlorines • ChE inhibitors • Organophosphates • Carbamates • Phenoxyherbicides • Pyrethroids • Bromine-based • Phenol- derivatives • Dipyridyl derivatives
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)
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)
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
Cholinesterase inhibitors • Organophosphates (OP) and Carbamates • Strong Acute neurotoxicity - AChE inhibition (cholinergic effects) • Nervous system toxins - nerve gas (sarin)
1st OP: TEPP (tetraethylpyrophosphate), followed by parathion 1st carbamic: 1930 WWII chemical warfare 1988 Iraq- against Kurds 1994 Japan 1995 Tokyo subway
Cholinesterase O O + CH3 C - O - CH2 - CH2 - N(CH3)3 CH3C-O- + HO-CH2-CH2-N(CH3)3 Esteratic Anionic +
X X R1-2 = e- withdrawing = aliphatic Organophosphates O R1 Parathion Malathion Soman Ecothiophate P R2