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 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.

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

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

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

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

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.

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 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

Nicotine Green 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