Mechanism of Pyrethroid Toxicity
Pyrethroids exert their primary toxic effects by prolonging the opening of voltage-gated sodium channels in nerve cells, causing repetitive nerve firing and eventual conduction block, with Type II pyrethroids additionally inhibiting chloride channels and GABA receptors at higher concentrations. 1, 2, 3
Primary Mechanism: Sodium Channel Disruption
Pyrethroids modify the gating kinetics of voltage-sensitive sodium channels by delaying their closure after activation. 1, 2 This creates a protracted sodium influx—termed a sodium "tail current"—that persists abnormally long after the initial depolarization. 1
Concentration-Dependent Effects
At low concentrations: The prolonged sodium tail current lowers the action potential threshold, causing repetitive nerve firing and hyperexcitability—this mechanism likely explains the characteristic paraesthesiae (tingling/burning sensations) seen with dermal exposure. 1
At high concentrations: The sodium tail current becomes so large that it prevents further action potential generation, resulting in "conduction block" and paralysis. 1
Sensory neurons are particularly vulnerable: Only very low pyrethroid concentrations are necessary to modify sensory neuron function, explaining why facial paraesthesiae are the most common occupational exposure symptom. 1
Type I vs Type II Pyrethroid Distinctions
The two pyrethroid classes produce different toxicity profiles based on their structural differences:
Type I Pyrethroids (lacking alpha-cyano group)
- Primary mechanism: Sodium channel modification alone 2
- Clinical presentation: Predominantly peripheral effects with tremor and hyperexcitability 2
Type II Pyrethroids (containing alpha-cyano group, e.g., cypermethrin, deltamethrin)
- Dual mechanism: Both sodium channel modification AND chloride channel inhibition 1, 2
- Chloride channel effects: Type II pyrethroids decrease chloride currents through voltage-dependent chloride channels, which contributes most significantly to their distinct toxicity profile 1
- GABA receptor antagonism: At relatively high concentrations, Type II pyrethroids also act on GABA-gated chloride channels, which is responsible for the seizures seen in severe Type II poisoning 1, 2
- Clinical presentation: More severe CNS effects including choreoathetosis (involuntary writhing movements), salivation, and seizures 2
Stereospecificity and Potency
Pyrethroid toxicity is highly stereospecific—different stereoisomers of the same compound have markedly different biological activities. 1, 4 The correlation between enhancement of sodium channel binding and insecticidal/toxic potency confirms that sodium channel disruption is the primary mechanism of action. 4
Additional Mechanisms Under Investigation
Recent research suggests pyrethroids may have effects beyond classical sodium channel disruption, though the clinical significance remains uncertain:
- Voltage-gated calcium channels: Some evidence suggests pyrethroids may affect calcium channels, potentially as a secondary mechanism 3
- Developmental neurotoxicity: Emerging data suggest potential effects on developing nervous systems, though evidence is currently equivocal 5
- Metabolite-mediated effects: Some pyrethroid metabolites may have independent toxic actions 5
Why Mammals Are Relatively Protected
Pyrethroids are approximately 2,250 times more toxic to insects than mammals due to several protective factors 1:
- Lower sodium channel sensitivity: Mammalian sodium channels are inherently less sensitive to pyrethroid binding 1
- Poor dermal absorption: Intact mammalian skin provides a significant barrier 1
- Rapid metabolism: Mammals quickly metabolize pyrethroids to non-toxic metabolites via esterase enzymes 1
Critical Caveat: Synergist Co-Formulation
When pyrethroids are co-formulated with piperonyl butoxide (a common synergist that inhibits metabolic degradation), mammalian toxicity increases substantially because the protective rapid metabolism is blocked. 1 This is clinically important when assessing commercial formulations rather than pure pyrethroid compounds.
Clinical Manifestations Explained by Mechanism
The sodium and chloride channel effects directly explain the clinical presentation:
- Paraesthesiae (facial tingling/burning): Hyperexcitability of cutaneous sensory nerve fibers from low-level sodium channel modification, exacerbated by heat, sunlight, or water 1
- Tremor and fasciculations: Repetitive nerve firing from sodium tail currents 2
- Seizures (Type II): GABA receptor antagonism and chloride channel inhibition at high concentrations 1, 2
- Coma and respiratory depression: Severe CNS sodium channel disruption causing conduction block 1