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
Neurological Effects of Pesticides
• Acute Effects
• Chronic effects
• Central effects
• Peripheral Effects
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
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
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.
TOCP in South Africa& Morocco
• Triortho-cresyl-phosphate a lubricating fluid additive sold in cooking oil
• 60 people suffered paralysis
• 10,000 people affected
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
Structure of the Nervous System
• Central Nervous system (CNS)
• Peripheral Nervous System (PNS)
– Special senses
– Peripheral sensory nerves
– Somatic motor fibers
– Autonomic nervous system
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
Pesticides Which Target the Nervous System
• Organophosphates/ Carbamates
• Organochlorines
• Pyrethroids
• Neonicotinoids
• Metals
• CNS Alpha receptor agonists
• CNS GABA Inhibitors
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
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
Toxicity of Cholinesterase Inhibitors Organophosphates /Carbamates
• Miosis
• Diaphoresis
• Salivation
• Lacrimation
• Urination
• Defecation
• Gastroenteric cramping
• Emessis
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
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.
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
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
Organochlorines
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.
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
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
NicotineGreen Tobacco Illness
• Dermal nicotine absorption
• Occurs in Tobacco Pickers
• Worse on Wet Days
• Nausea, headache, tremor,
• Weakness, fasciculation
Nicotinic Symptoms
– Fasciculations– Temor– Weakness– Paralysis– Hypertension– Diaphoresis– Nausea
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.
Metals
• Lead Arsenate
• Mercury
• Organotin compounds
• Manganese containing compounds
• Thallium
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
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
Organotin compounds
• Used as antifouling agents in marine paints
• Also used as fungicides
CNS is primary target:
Headache, photophobia, convulsions, loss of consciousness.
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.
Thallium
• Used as a rodenticide
• A light metal treated like potassium by the body
• Broadly toxic metal to many tissues
• Severe painful peripheral neuropathy
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.
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
Parkinson’s Disease
• Manganese containing Pesticides include– Farmaneb, Manesan, Manex, Manzate, Nereb,
and Newspor
• Carbon Disulfide (a fumigant)
• Possibly OP’s
• Paraquat
• Possibly Rotenone
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•
Something to Think About