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