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#148

  1. 1. Neurological Effects of Pesticides <ul><li>Matthew Keifer MD MPH </li></ul><ul><li>Associate Professor Medicine and Environmental Health Sciences </li></ul><ul><li>University of Washington </li></ul><ul><li>Director, International Scholars in Occupational and Environmental Health </li></ul>
  2. 2. Neurological Effects of Pesticides <ul><li>Acute Effects </li></ul><ul><li>Chronic effects </li></ul><ul><li>Central effects </li></ul><ul><li>Peripheral Effects </li></ul>
  3. 3. Neurological Effects <ul><li>Big Disasters-Famous events </li></ul><ul><li>The pesticides that target the nervous system </li></ul><ul><li>Cholinesterase inhibitors </li></ul><ul><li>Organochlorines </li></ul><ul><li>Metal based pesticides </li></ul><ul><li>New Pesticides </li></ul><ul><li>Others with suspected neurological effect </li></ul><ul><li>Open questions </li></ul>
  4. 4. Famous Events Neurological Pesticide History <ul><li>Mercury flour consumed in Iraq </li></ul><ul><ul><li>In 1956 and again in 1961 households consumed Mercury treated flour </li></ul></ul><ul><ul><li>Over 100 died and many were left with permanent neurological damage </li></ul></ul><ul><ul><li>Mercury treated wheat seed 1971. Methyl mercury treated grain used for bread. 50 thousands poisoned, 5 thousand dead. </li></ul></ul><ul><li>Mercury in Guatemala </li></ul><ul><ul><li>Poor families consumed methyl mercury treated seeds in 1963-64. </li></ul></ul><ul><ul><ul><li>Tens of children poisoned. </li></ul></ul></ul><ul><li>Alamagordo New Mexico </li></ul><ul><ul><li>A family consumed pigs fed organomercurials. </li></ul></ul><ul><ul><li>Two children remain in coma, an in utero child developed an evolving neurological syndrome with hypotonia, irritability and nystagmus </li></ul></ul>
  5. 5. Ginger Jake Not a Pesticide Incident <ul><li>The Ginger Jake Outbreak </li></ul><ul><ul><li>Tri-Ortho Cresyl Pyrophosphate (TOCP) </li></ul></ul><ul><ul><ul><li>Lindol (TOCP containing solvent) </li></ul></ul></ul><ul><ul><ul><li>Added to Jake, a popular ginger flavored concoction </li></ul></ul></ul><ul><ul><ul><li>Thousands, potentially 50,000 people developed peripheral and central long tract disease. </li></ul></ul></ul><ul><ul><ul><li>The event became folklore </li></ul></ul></ul><ul><ul><ul><li>30 years later, survivors still affected </li></ul></ul></ul><ul><ul><ul><li>“Jake Leg” 13 folk songs describe it. </li></ul></ul></ul>
  6. 6. TOCP in South Africa & Morocco <ul><li>Triortho-cresyl-phosphate a lubricating fluid additive sold in cooking oil </li></ul><ul><li>60 people suffered paralysis </li></ul><ul><li>10,000 people affected </li></ul>
  7. 7. Kepone Zombies <ul><li>A cohort of workers in Hopewell VA at a Chlordecone factory, exposed to work conditions which resulted in significant over-exposure </li></ul><ul><li>Chlordecone toxicity </li></ul><ul><ul><li>Tremors, anxiety, irritability, memory loss </li></ul></ul><ul><ul><li>Myoclonic jerking, ataxia </li></ul></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>One rock group and one Dead Kennedy’s song </li></ul></ul>
  8. 8. Structure of the Nervous System <ul><li>Central Nervous system (CNS) </li></ul><ul><li>Peripheral Nervous System (PNS) </li></ul><ul><ul><li>Special senses </li></ul></ul><ul><ul><li>Peripheral sensory nerves </li></ul></ul><ul><ul><li>Somatic motor fibers </li></ul></ul><ul><ul><li>Autonomic nervous system </li></ul></ul>
  9. 9. Nervous System is Vulnerable <ul><li>Limited regenerative capacity </li></ul><ul><ul><li>Damage may not be repaired </li></ul></ul><ul><li>High metabolic demand </li></ul><ul><ul><li>Lots of blood flow </li></ul></ul><ul><ul><li>Low metabolic reserve </li></ul></ul><ul><li>Big surface area </li></ul><ul><li>High lipid content </li></ul>
  10. 10. Pesticides Which Target the Nervous System <ul><li>Organophosphates/ Carbamates </li></ul><ul><li>Organochlorines </li></ul><ul><li>Pyrethroids </li></ul><ul><li>Neonicotinoids </li></ul><ul><li>Metals </li></ul><ul><li>CNS Alpha receptor agonists </li></ul><ul><li>CNS GABA Inhibitors </li></ul>
  11. 11. Organophosphates and Carbamates <ul><li>Cholinesterase is found in the nerve junction </li></ul><ul><li>It turns off the chemical messenger that tells muscles, glands and nerves to function </li></ul><ul><li>When it is inhibited the messenger builds up and overstimulates muscles, glands and nerves </li></ul>
  12. 12. Organophosphates The Target: Cholinesterase <ul><li>Essential for nervous system function </li></ul><ul><li>Important in voluntary muscles, autonomic & central nervous system </li></ul><ul><li>The target of a specific group of widely used pesticides </li></ul><ul><li>Measurable in blood </li></ul>
  13. 13. Toxicity of Cholinesterase Inhibitors Organophosphates /Carbamates <ul><li>M iosis </li></ul><ul><li>D iaphoresis </li></ul><ul><li>S alivation </li></ul><ul><li>L acrimation </li></ul><ul><li>U rination </li></ul><ul><li>D efecation </li></ul><ul><li>G astroenteric cramping </li></ul><ul><li>E messis </li></ul>
  14. 14. Organophosphate Induced Peripheral Neuropathy <ul><li>Rare complication of a few pesticides </li></ul><ul><li>Generally believed to require high level intoxication </li></ul><ul><li>Inhibition of Neuropathy Target Esterase (NTE) </li></ul><ul><li>Primarily Motor </li></ul><ul><li>Onset at 2 weeks </li></ul><ul><li>Pain followed by weakness in legs </li></ul><ul><li>Loss of reflexes, Flaccid paralysis </li></ul>
  15. 15. Persistent CNS Effects after Acute OP Poisoning <ul><li>Altered attention, memory, higher cognitive function </li></ul><ul><li>Reported by patients and families </li></ul><ul><li>Four Population Investigations Support this </li></ul><ul><li>Savage, Rosenstock, Steenland Wesseling </li></ul><ul><li>Chronic low level exposure Does not appear to do this. A few studies to the contrary. </li></ul><ul><li>“ COPIND” chronic organophosphate induced neuropsychiatric disorders. </li></ul>
  16. 16. Long-Term Effects of Acute Organophosphate Poisonings <ul><li>The British Ministry of Health, 1999 </li></ul><ul><ul><li>“Neuropsychological abnormalities can occur as a long-term complication of acute OP poisoning” </li></ul></ul><ul><ul><li>“Peripheral neuropathy .. Is a well established complication of poisonings by OPs that inhibit Neuropathy Target Esterase” </li></ul></ul><ul><ul><li>Other OPs can do similarly but the neuropathy is less severe </li></ul></ul>
  17. 17. OP-induced Intermediate Syndrome <ul><ul><li>Proximal muscle weakness </li></ul></ul><ul><ul><li>Respiratory paralysis (may require respiratory support) </li></ul></ul><ul><ul><li>May be due to cholinesterase inhibition </li></ul></ul><ul><ul><li>May be due to receptor exhaustion </li></ul></ul><ul><ul><li>Thought to be a rare outcome </li></ul></ul><ul><ul><ul><ul><li>Senanayake 1982 </li></ul></ul></ul></ul><ul><ul><li>Only in severe intoxications </li></ul></ul>
  18. 18. Organochlorines
  19. 19. Organochlorines DDT, Cyclodienes, Lindane <ul><li>Interfere with sodium-channel gating of neurons. </li></ul><ul><li>Destabilize membranes. </li></ul><ul><li>Cause uncontrolled depolarization of nervous tissue. </li></ul><ul><li>Acute effects </li></ul><ul><ul><li>Seizures, Myoclonic Jerking, Coma </li></ul></ul><ul><li>Chronic Effects: </li></ul><ul><ul><li>Some reports of Long-Term CNS changes from prolonged DDT use. </li></ul></ul>
  20. 20. Parasthesias and Pyrethroids <ul><li>Interfere with sodium channel gating in nervous tissue. </li></ul><ul><li>Acute symptoms include tingling and burning </li></ul><ul><li>Usually acral parasthesias </li></ul><ul><li>Mucous membranes affected if exposed </li></ul><ul><li>High dose may result in clonic spasm or tremors </li></ul><ul><li>No evidence to date of long term neurological effects </li></ul>
  21. 21. Fumigants <ul><li>Methyl Bromide </li></ul><ul><ul><li>Acute central nervous system effects </li></ul></ul><ul><ul><ul><li>Ataxia, tremor, slurred speech, coma. </li></ul></ul></ul><ul><ul><li>May result in persistent myoclonic jerking, tremors and behavioral disturbances. </li></ul></ul><ul><ul><li>May result in death. </li></ul></ul><ul><li>Carbon Disulfide </li></ul><ul><ul><li>Parkinsons </li></ul></ul><ul><li>Hydrogen Cyanide </li></ul><ul><ul><li>Death </li></ul></ul>
  22. 22. Nicotine Green Tobacco Illness <ul><li>Dermal nicotine absorption </li></ul><ul><li>Occurs in Tobacco Pickers </li></ul><ul><li>Worse on Wet Days </li></ul><ul><li>Nausea, headache, tremor, </li></ul><ul><li>Weakness, fasciculation </li></ul>
  23. 23. Nicotinic Symptoms <ul><ul><li>Fasciculations </li></ul></ul><ul><ul><li>Temor </li></ul></ul><ul><ul><li>Weakness </li></ul></ul><ul><ul><li>Paralysis </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Diaphoresis </li></ul></ul><ul><ul><li>Nausea </li></ul></ul>
  24. 24. Neonicotinoids <ul><li>Imidocloprid (Admire, Condifor, Gaucho, Premier) </li></ul><ul><ul><li>Stimulates Nicotinic receptors. </li></ul></ul><ul><ul><li>Few human poisonings as yet. </li></ul></ul><ul><ul><li>Expected to cause nicotinic symptoms. </li></ul></ul><ul><ul><li>No long term effects reported as yet. </li></ul></ul>
  25. 25. Metals <ul><li>Lead Arsenate </li></ul><ul><li>Mercury </li></ul><ul><li>Organotin compounds </li></ul><ul><li>Manganese containing compounds </li></ul><ul><li>Thallium </li></ul>
  26. 26. Lead Arsenate <ul><li>To control gypsy moth in 1892. </li></ul><ul><li>Widely used until 1940s. </li></ul><ul><li>Still contaminates agricultural land. </li></ul><ul><li>CCA a wood preservation, to be removed. </li></ul><ul><li>Both Lead and Arsenic are neurotoxins </li></ul><ul><ul><li>Both cause peripheral neuropathy </li></ul></ul><ul><ul><li>Both cause central nervous system effects if high enough concentration achieved </li></ul></ul>
  27. 27. Organomercury compounds <ul><li>Rarely used today as a pesticide </li></ul><ul><li>Past experience shows it dramatic neurotoxicity </li></ul><ul><ul><li>Mania </li></ul></ul><ul><ul><li>Withdrawal, memory loss, vasomotor disturbances </li></ul></ul><ul><ul><li>Visual disturbances </li></ul></ul><ul><ul><li>Disarthria </li></ul></ul><ul><ul><li>Tremor </li></ul></ul><ul><ul><li>Spontaneous abortion, neurological effects on fetus </li></ul></ul>
  28. 28. Organotin compounds <ul><li>Used as antifouling agents in marine paints </li></ul><ul><li>Also used as fungicides </li></ul><ul><li>CNS is primary target: </li></ul><ul><li>Headache, photophobia, convulsions, loss of consciousness. </li></ul>
  29. 29. Manganese Fungicides <ul><li>Ethylene Bis Dithiocarbamates </li></ul><ul><ul><li>Maneb, Mancozeb </li></ul></ul><ul><ul><li>Generally low acute toxicity </li></ul></ul><ul><ul><li>Have been associated with Parkinsonian syndrome in pesticide exposed workers </li></ul></ul><ul><ul><li>Consistent with manganese poisoning in miner and smelters. </li></ul></ul>
  30. 30. Thallium <ul><li>Used as a rodenticide </li></ul><ul><li>A light metal treated like potassium by the body </li></ul><ul><li>Broadly toxic metal to many tissues </li></ul><ul><li>Severe painful peripheral neuropathy </li></ul>
  31. 31. Alpha-2 Receptor Stimulants <ul><li>Amitraz (Baam, Aazdieno, Acarac, Mitac) </li></ul><ul><ul><li>Few human cases </li></ul></ul><ul><ul><li>Appears to simulate an overdose of Clonidine </li></ul></ul><ul><ul><li>Bradycardia, hypotension, hypothermia, hyperglycemia. </li></ul></ul><ul><ul><li>Myosis, mydriasis coma. </li></ul></ul><ul><ul><li>CNS depression. </li></ul></ul><ul><ul><li>No long term effects described in animal testing or in humans so far. </li></ul></ul>
  32. 32. GABA-blockers <ul><li>Fibrinil. </li></ul><ul><li>Block the GABA-gated chloride channel. </li></ul><ul><ul><li>Also some old favorites: Alpha-endosulfan, lindane, picrotoxin </li></ul></ul><ul><ul><li>Seizure inducing in high dose. </li></ul></ul><ul><ul><li>New GABA blockers are more active but more discriminating for insect GABA receptors. </li></ul></ul><ul><ul><li>The metabolic activation to the </li></ul></ul>
  33. 33. Parkinson’s Disease <ul><li>Manganese containing Pesticides include </li></ul><ul><ul><li>Farmaneb, Manesan, Manex, Manzate, Nereb, and Newspor </li></ul></ul><ul><li>Carbon Disulfide (a fumigant) </li></ul><ul><li>Possibly OP’s </li></ul><ul><li>Paraquat </li></ul><ul><li>Possibly Rotenone </li></ul>
  34. 34. Research Challenges <ul><li>Questions </li></ul><ul><li>Do pesticides cause: </li></ul><ul><li>[] Parkinson’s? </li></ul><ul><li>[] ALS? </li></ul><ul><li>[] Alzheimers? </li></ul><ul><li>[] developmental delay? </li></ul><ul><li>What are the culture free tests that identify neurobehavioral problems? </li></ul><ul><li>How do we address the low-level exposure question </li></ul><ul><li>Most are relatively rare diseases </li></ul><ul><li>Exposure quantification is the key </li></ul>
  35. 35. Something to Think About

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