Mode of Action

Pyrethrins, pyrethroids, DDT and DDT analogs belong to a group of chemicals that are neurotoxic and share a similar mode of action that is distinctive from other classes of insecticides. There are several ways that pyrethrins and pyrethroids can enter the body of an organism to exert their effects. The first mode is non-stereospecific with rapid penetration through the epidermis, followed by uptake by the blood or hemolymph carrier proteins and subsequent distribution throughout the body. Pyrethroid diffusion along the epidermis cells is the main route of distribution to the central nervous system (CNS) after penetration.37 Pyrethroids also can enter the CNS directly via contact with sensory organs of the peripheral nervous system. The sensory structures of both invertebrates and vertebrates are sensitive to pyrethroids.38 Pyrethroids can also enter the body through the airway in the vapor phase, but such penetration represents only a small contribution due to the low vapor pressure of pyre-throids (see Table 3.3). Pyrethroids can also be ingested, and penetration into the blood-hemolymph through the alimentary canal can play an important role in toxicity.

Pyrethroids have been classified toxicologically into two subclasses based on the induction of either whole body tremors (T syndrome) or a coarse whole body tremor progressing to sinuous writhing (choreoathetosis) with salivation (CS syndrome) following near-lethal dose levels in both rats (Rattus norvegicus) and mice (Mus musculus), and closely follows the chemical structure of the two types of pyrethroids.39,40 Type I pyrethroids are characterized by the T-syndrome which consists of aggressive sparring, sensitivity to external stimuli, fine tremors progressing to whole body tremors and prostration. Type I pyre-throids also elevate core body temperature, which is attributed to the excessive muscular activity associated with tremors. Type II pyrethroids are characterized by the CS syndrome which is comprised initially of pawing and burrowing behavior followed by profuse salivation, choreoathetosis, increased startle response, and terminal chronic seizures. Type II pyrethroids decrease core body temperature, which is attributed to excessive salivation and wetting of the ventral body surface. Although salivation typically co-occurs with choreoathetosis, a TS syndrome (tremor with salivation) has also been observed in a few pyrethroids. Multiple lines of evidence show that pyrethroids, as a class, do not act in a similar fashion on the voltage-gated sodium channels, and the classifications of toxicology are not absolute for either invertebrates or vertebrates.41,42 For example, the type I pyrethroid, bioallethrin, exhibits toxicological symptoms of both type I and II intoxication.

As expected, increasing the dose levels of pyrethrins and pyrethroids results in a proportional increase in motor activity, which is the classic dose-response effect with respect to neurotoxic substances. Pyrethrins and pyrethroids act very quickly to produce symptoms of lost coordination and paralysis which are known as ''the knockdown effect'', and which are often accompanied by spasms and tremors that induce intense repetitive activation in sense organs and in myelinated nerve fibers. The spasms can be violent and can cause the loss of extremities, such as legs and wings in insects.

The most compelling evidence of a similar mode of action for pyrethrins, pyrethroids, and DDT comes from resistance studies examining knockdown resistance (kdr) demonstrating cross resistance. Physiological and biochemical studies of pyrethrins, pyrethroids and DDT show that in both vertebrates and invertebrates the primary mode of action is the binding of the voltage-gated sodium channel.38,42 44 Mammals, unlike insects, however, have multiple iso-forms of the sodium channel that vary by tissue type, as well as biophysical and pharmacological properties.45

To understand the primary mode of action, the mechanism by which voltage-gated sodium channels work needs to be reviewed. When the voltage-gated sodium channel is stimulated, it causes a depolarization of the membrane, which changes the nerve cell's permeability to Na1 and K1. The excited membrane becomes permeable to Na1, with a small number of ions acted on when electrical and concentration gradients rush into the membrane causing the depolarization of the membrane. The sodium ions carry a current inward, which is referred to as the ''action potential''. The inward movement of sodium ions causes the membrane potential to overshoot the membrane potential with the inside becoming positive relative to the outside of the membrane surface. During a spike, the membrane is absolutely refractory, and a stimulus of even greater magnitude cannot cause the gates to open wider or more Na1 to flow inward. In addition, a neuron is partially refractory for a further few milliseconds and only a strong stimulus will cause a new response.46 The upper limit of impulses per second is about 100, with each depolarization event lasting only about two to three milliseconds.46 Pyrethrins and type I pyrethroids modify the sodium channels such that there is a slight prolongation of the open time (i.e. sodium tail currents of approximately 20 milliseconds), which results in multiple long action potentials. Type II pyrethroids significantly prolong channel open time (i.e. sodium tail currents of 200 milliseconds to minutes), resulting in an increased resting membrane potential and often inducing a depolarization-dependent block of action potentials.

Type I pyrethroids cause multiple spike discharges, while type II pyrethroids cause a stimulus-dependent depolarization of the membrane potential which reduces the amplitude of the action potential, and a loss of electrical excitability in both vertebrates and invertebrates.38,47 The toxic action is exerted by preventing the deactivation or closing of the gate after activation and membrane depolarization. This results in destabilizing the negative after potential of the nerve due to the leakage of Na1 ions through the nerve membrane. This causes hyperactivity by delaying the closing sodium channels which allows a persistent inward current to flow after the action potential, causing repetitive discharges that can occur either spontaneously or after a single stimulus. The sodium channel residue that is critical for regulating the action of pyrethroids is the negatively-charged aspartic acid residue at position 802 located in the extracellular end of the transmembrane segment 1 of domain II, which is critical for both the action of pyrethroids and the voltage dependence of channel

activation.48

The differences between type I and II pyrethroids are expressed in the motor nerve terminals, where type I cause presynaptic repetitive discharges, and type II cause a tonic release of transmitter indicative of membrane depolariza-tion.38,49 Type II pyrethroids are a more potent toxicant than type I in depolarizing the nerves.49 Type II pyrethroids are associated with faster activation-deactivation kinetics on the Nav1.8 sodium channels than type I pyrethroids in vertebrates.42 The higher toxicity of type II pyrethroids is mostly attributed to the hyperexcitatory effect on the axons which results from their stronger membrane depolarizing action. Type I pyrethroids modify the sodium channels in the closed state, while type II pyrethroids modify the open but not inactivated sodium channels.50 However, this relationship does not always hold true; cis-permethrin and fenvalerate interact with both closed and open sodium channels, but they bind with greater affinity to the open state.51 53 Type I repetitive discharges have been shown to be suppressed by cypermethrin, indicating that the two pyrethroid types can interact antagonistically.53

Pyrethroids affect the voltage-sensitive calcium channels, g-aminobutyric acid (GABA) receptors and GABA-activated channels, and voltage-sensitive chloride channel.43,54 Recent findings suggest that pyrethroids can modulate the activity of voltage-gated calcium (Ca21) channels.55 However, these studies report conflicting results on the inhibitory effects of pyrethroids on voltage-gated calcium channels. Neal et al.56 demonstrated that allethrin significantly altered the voltage dependency of activation and inactivation of L-type voltage-gated calcium channels, which suggests that differential modulation of voltage-gated calcium channels subtypes could elucidate some of the conflicting observations of other studies. Type II pyrethroids are more potent enhancers of Ca21 influx and glutamate release under depolarizing conditions than type I pyrethroids.41,51

The GABA receptor-chloride ionophore complex is also a target of type II pyrethroids. GABA is an inhibitory transmitter in the synapse of the CNS of both vertebrates and invertebrates. Pretreatment with diazepam (a benzodi-azepine anticonvulsant known to act on the GABA receptors) has been shown to selectively delay the onset of toxic symptoms of type II, but not type I, pyrethroids in cockroaches and mice.38 Radioligand binding studies have shown that deltamethrin, but not its non-toxic a-R-cyano epimer, inhibited [3H]dihydropicrotoxin binding to the chloride ionophore in the rat brain GABA receptor complex.38 Pyrethrins and pyrethroids also inhibit the Cl_ channel function at the GABA receptor-ionophore complex.57

An additional target proposed for type II pyrethroids is the membrane chloride ion channel.58 Generally type II pyrethroids decrease the open channel probability of chloride channels, but the type I pyrethroids do not seem to have an effect on the chlorine channel.42,54,59 Upon further investigation, Burr and Ray59 found that the type I pyrethroid bioallethrin, and type II pyrethroids p-cyfluthrin, cypermethrin, deltamethrin and fenpropathrin, significantly decreased the probability that the ligand-gated chloride channel would be an open channel. However, they found that the type I pyrethroids, bifenthrin, bioresmethrin, cis-permethrin and cis-resmethrin, and the type II pyrethroids, cyfluthrin, lambda-cyhalothrin, esfenvalerate and tefluthrin, did not. Interestingly, the type I pyrethroid, bioallethrin, significantly alters the probability of opening the ligand-gated chloride channel, but has generally a weaker response than type II pyrethroids.42 One hypothesis was that bioallethrin may be a mixed-type pyrethroid.43,59 The blockade of the voltage-sensitive chloride channels is associated with salivation, which is a hallmark of type II pyrethroid intoxication and could contribute to the enhanced excitability of the CNS.43

Pyrethroids inhibit the Ca-ATPase, Ca-Mg ATPase neurotransmitters and the peripheral benzodiazepine receptors,60 but their action on these sites is minor compared with the voltage-gated sodium channels. The effects on these sites could, however, enhance the uncontrolled convulsions and tremors.43

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