Pesticide Toxicology
Week 2:
Organophosphate Insecticides
a. Acute toxicity
Categories of Effects
• Muscarinic
– Mimic action of muscarine
• Peripheral nervous system only
– Smooth muscle, heart, exocrine glands
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Bronchoconstriction, salivation, lacrimation, perspiration
Nausea, vomiting, diarrhea, cramps
Urination, defecation
Bradycardia, miosis
• Nicotinic
– Mimic action of nicotine
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Neuromuscular junction of voluntary muscles
Muscle weakness (including respiratory muscles)
Twitching, cramps, pallor
Elevated blood pressure, tachycardia
• CNS symptoms
– Confusion, restlessness, irritability, slurred speech,
– Insomnia, emotional instability
– Coma
Time Course of Toxicity
• Onset of symptoms
– Minutes
• Sarin, parathion, TEPP
– Hours
• EPN
– Days
• Chlorpyrifos
• Abatement of symptoms
– Slow onset tends to mean slow abatement
– Acute symptoms rarely last more than a few days
• Regeneration of AChE takes ~ 1 month
– Ample opportunity for re-intoxication
Chronic Effects of OPs: OPIDN
• Organophosphate-induced delayed neuropathy
(neurotoxicity)
• Caused by subset of AChE-inhibiting OPs but not
due to AChE inhibition
• Delayed onset
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Symptoms begin 7-30 days after exposure
Recovery continues up to 1 year
Permanent effects
Longest axons most vulnerable
• Mechanism
– Inhibition of neurotoxic esterase
– Axonal damage
– Death of neuron
OPIDN: Organophosphorus ester-induced
delayed neuropathy
Leptophos (Phosvel™)
• Dying back axonopathy
• It is not due to inhibition of AChE
(acetylcholinesterase)
• Only compounds that can inhibit AChE
cause it.
– So it is presumably an esterase
• May result from single exposure
– Or from multiple smaller exposures
• Irreversible
• Rats and mice do not become paralyzed
• Adult hens become paralyzed
– Chicks do not.
• Human children do become paralyzed
• An estimated 100,000 people worldwide
have been affected
Leptophos:
How Not to Identify a Neurotoxicant
Case history on website deals more
with the regulatory process than with
toxicology.
Chronic Effects of OPs: Reproductive
Toxicity
• Avian
– Subset of OPs
– Inhibition of AChE
– Inhibition of kynurenine formamidase
• Mammalian
– No physical defects due to AChE inhibition
– Human evidence for developmental CNS damage
• Chlorpyrifos (Dursban)
– Delayed neuropathy also causes erectile dysfunction
Chronic Effects of OPs:
Miscellaneous
• Intermediate syndrome
– Subset of insecticidal OPs
– Onset delayed for several days
– Not OPIDN
– Recovery?
• Long-term CNS effects
– Epidemiological evidence
– Documented by EEG after sarin exposure
• Gulf War syndrome?
Regulatory Aspects of OP Toxicity
• What is the measure of toxicity
– Symptoms
– AChE inhibition
– ChE inhibition
Ecotoxicology
• Chemical attributes
– Persistence
– Potential for bioaccumulation
• Ecosystem effects
– Secondary poisoning
– Temporary changes in ecosystem
– Permanent changes in ecosystem
• Ecosystem simplification
• Stressed ecosystems
– Reproductive toxicology
• Non-mammalian species
– Evolutionary consequences of efforts at extermination
Bioaccumulation and Persistence
• OPs are
– More water soluble than OCs
– Less persistent
• Days or months, not years
– Malathion (outdoors)
– Bioaccumulation is unlikely
Secondary poisoning
• May result from
– Rapid lethality + residue
• Fenthion used as avicide
– LD50
» 5 mg/kg in birds
» 250 mg/kg in rats
– Weakened target
• Cooper’s hawk in S America
– Hard to detect
• Small dead organisms disappear fast
Temporary changes in ecosystem
composition
• Insecticides kill insects
– Disrupts food supply for
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Insects
Fish
Mammals
Birds
• Agricultural applications occur during spring
– primary breeding season
• Single applications should be repairable
Reproductive toxicity
• Difficult to assay
– Stage-specific
– Species-specific
• Historical Examples
– Organochlorines
• DDT thins birds’ eggshells
• PCBs cause malformations
• Dioxin-like chemicals cause GLEMEDS in trout
– OPs
• Malformations in birds
– Sprayed on quail eggs
– Site specific, not global
• Local effects repairable if no other stresses occur
Ecosystem Simplification
• Elimination of already stressed species
• Destruction of habitat
– Herbicides
– Large-scale agriculture
– Monocultures
– Lack of hedgerows
Consequences of evolutionary
pressures
• Resistance
– Degradation of chemical
– Insensitivity to chemical
– Blocking entry of chemical
Other
– Western corn rootworm
• Dieldrin
• Migration rate?
– Crop rotation
• Overwintering cycle
• Egg laying behavior
– Malaria control and mosquito behavior