Neurological Effects of Pesticides

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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

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Neurological Effects of Pesticides

• Acute Effects
• Chronic effects
• Central effects
• Peripheral Effects

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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

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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

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Ginger JakeNot 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.

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TOCP in South Africa Morocco

• Triortho-cresyl-phosphate a lubricating fluid
  additive sold in cooking oil
• 60 people suffered paralysis
• 10,000 people affected

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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 Kennedys song

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Structure of the Nervous System

• Peripheral Nervous System (PNS)
• Special senses
• Peripheral sensory nerves
• Somatic motor fibers
• Autonomic nervous system

• Central Nervous system (CNS)

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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

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Pesticides Which Target the Nervous System

• Organophosphates/ Carbamates
• Organochlorines
• Pyrethroids
• Neonicotinoids
• Metals
• CNS Alpha receptor agonists
• CNS GABA Inhibitors

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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

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OrganophosphatesThe 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

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Toxicity of Cholinesterase Inhibitors
Organophosphates /Carbamates

• Miosis
• Diaphoresis
• Salivation
• Lacrimation
• Urination
• Defecation
• Gastroenteric cramping
• Emessis

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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

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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.

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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

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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

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Organochlorines
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OrganochlorinesDDT, 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.

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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

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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

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NicotineGreen Tobacco Illness

• Dermal nicotine absorption
• Occurs in Tobacco Pickers
• Worse on Wet Days
• Nausea, headache, tremor,
• Weakness, fasciculation

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Nicotinic Symptoms

• Fasciculations
• Temor
• Weakness
• Paralysis
• Hypertension
• Diaphoresis
• Nausea

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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.

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Metals

• Lead Arsenate
• Mercury
• Organotin compounds
• Manganese containing compounds
• Thallium

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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

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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

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Organotin compounds

• Used as antifouling agents in marine paints
• Also used as fungicides
• CNS is primary target
• Headache, photophobia, convulsions, loss of
  consciousness.

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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.

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Thallium

• Used as a rodenticide
• A light metal treated like potassium by the body
• Broadly toxic metal to many tissues
• Severe painful peripheral neuropathy

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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.

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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

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Parkinsons Disease

• Manganese containing Pesticides include
• Farmaneb, Manesan, Manex, Manzate, Nereb, and
  Newspor
• Carbon Disulfide (a fumigant)
• Possibly OPs
• Paraquat
• Possibly Rotenone

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Research Challenges

• Questions
• Do pesticides cause
• Parkinsons?
• 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

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Something to Think About