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 Methyl mercury treated grain used for bread. 50 thousands poisoned, 5 thousand dead.
Mercury in Guatemala
Poor families consumed methyl mercury treated seeds in
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
Peripheral Nervous System (PNS)
Special senses
Peripheral sensory nerves
Somatic motor fibers
Autonomic nervous system
Central Nervous system (CNS)

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
Miosis
Diaphoresis
Salivation
Lacrimation
Urination
Defecation
Gastroenteric cramping
Emessis

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 Carbon Disulfide Hydrogen Cyanide
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