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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

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