For educational purposes only.
Washington University School of Medicine, St. Louis, MO

TOXIC NEUROPATHIES
  resulting from
Organophosphate Pesticides

TOXIC NEUROPATHIES: CLINICAL & PATHOLOGICAL FEATURES

Axonal:   Sensory & Motor:  Organophosphates

Organophosphorous Esters

• Uses: Insecticides; Petroleum additives; Flame retardants; War gases
• Absorbed through skin, respiratory, GI tract
• Lab marker: ¯ erythrocyte acetylcholinesterase activity
• Toxins:
  • chlorpyrifos: Sensory neuropathy; Memory loss
  • leptophos
  • methamidophos: Non-aging NTE inhibitor
  • metrifonate
  • mipafox
  • parathion
  • trichlorphonate;
  • Triorthocresyl phosphate (TOCP)
• Clinical syndromes
  • Acute Toxicity: Cholinesterase inhibition
  • Intermediate syndrome: ? Excitotoxicity at neuromuscular [affecting or characteristic of both neural and muscular tissue] junctions
    • Onset: 1 to 3 days
    • Proximal [situated nearest to point of attachment or origin] weakness; Respiratory failure; Cranial [of or relating to the cranium which encloses the brain] neuropathy [disease of the nervous system]
    • Duration: 2 to 3 weeks
  • Neuropathy [an abnormal and usually degenerative state of the nervous system or nerves; also : a systemic condition that stems from a neuropathy]
    • Onset: Delayed 7 to 12 days following single exposure
    • Motor  [involving or relating to movements of the muscles]
      & sensory [of a nerve fiber or impulse originating outside and passing toward the central nervous system; related to the senses]
    • Distal [away from point of attachment or origin]
    • Axonal [relating to an axon, the long nerve fiber that conducts away from the cell body of the neuron]
  • Myelopathy [a disease or disorder of the spinal cord or bone marrow]
• Mechanism of action: See TOCP

Triorthocresyl phosphate (TOCP)

• Uses: Plastic softener; High temperature lubricant
• Toxicity
  • Organophosphorous ester
  • Ingestion; also skin contact, inhalation
    • Jamaica ginger extract (jake leg paralysis)
    • Morocco: Contaminated cooking oil
    • Sri Lanka: adulterated gingli oil
  • Toxic mechanisms: 2 associated processes
    • Phosphorylation of nervous system esterases
      • Especially neurotoxic esterase (NTE)
    • "Aging" of the phosphoryl-enzyme complex
      • Cleavage of chain from bound phosphorous atom
        
      • Leaves - charged monosubstituted phosphoryl residue at active site
        
      • Delayed neuropathy more common with "aging" agents
        • Only with organophosphorous compounds that age
  • Toxicity limited by activity of paraoxonases
• Onset: Single large exposure
  • Transient (1 day) cholinergic [Releasing or activated by acetylcholine] response
    • Diarrhea; Perspiration; Fasciculations [muscular twitching of contiguous groups of muscle fibers]
  • Other organophosphate esters
    • May be rapidly fatal with more potent anti-cholinesterase properties
  • Chronic exposure: No cholinergic [releasing or activated by acetylcholine] symptoms
• Neuropathy
  • Onset
    • 7 to 12 days after exposure
    • Cramping pain in calves
    • Tingling & burning in feet ± hands
  • Motor > Sensory
  • Weakness: Distal [away from point of attachment or origin]; Feet then hands then proximal [situated nearest to point of attachment or origin]
  • Course: Maximum severity after 2 weeks
  • Recovery: Residual [remaining in effect after the inciting incident] distal  
    [away from point of attachment] weakness
    & spasticity [the quality of moving or acting in spasms; a spastic state or condition; especially: muscular hypertonicity or increased tension with increased tendon reflexes]
  • Incidence: Variable [something that is likely to vary; something that is subject to variation]
  • Electrophysiology: Axonal [relating to an axon, the long nerve fiber that conducts away from the cell body of the neuron];
    Distal [away from point of attachment]
  • CSF: Unremarkable
  • Pathology [the structural and functional deviations from the normal that constitute disease or characterize a particular disease]:
  • Distal axonopathy [disease of the axon the long nerve fiber that conducts away from the cell body of the neuron] in PNS [peripheral nervous system] & CNS [central nervous system]
• Myelopathy [a disease or disorder of the spinal cord or bone marrow]
  • Spasticity [the quality of moving or acting in spasms; a spastic state or condition; especially: muscular hypertonicity or increased tension with increased tendon reflexes]: Legs > arms
  • Becomes apparent when neuropathy recovers
• Ataxia [an inability to coordinate voluntary muscular movements that is symptomatic of some neurological disorders; unsteady movements and staggering gait]

11/30/98