much slower than oral or inhalation exposure, and less than 2% of the applied dose is absorbed. Once absorbed, pyrethroids are distributed to most tissues, especially to those with a high lipid concentration. Pyrethroids are metabolized mainly via ester hydrolysis and oxidation at several loci of the structure. For example, permethrin is detoxified to at least 80 metabolites, including products hydroxylated at the cis and trans methyl groups (Casida et al., 1983). Metabolic enzymes include esterases and P450s. Most of the metabolites are inactive. Half-life varies among the different pyrethroid compounds, but range from 6.4 to 16.5 h in humans, with the elimination mostly complete within 5 d (ATSDR, 2001b). The metabolites are generally excreted as alcohols, phenols, carboxylic acids, and their glycine, sulfate, glucuronide and glucoside conjugates (ATSDR, 2001b).
No information specific to pyrethroids is available on genetic polymorphisms. Young rats have been shown to be more sensitive than adults to an acute lethal dose of type II pyrethroids, but no differences in age-related sensitivity were seen in response to lower doses. No age differences in sensitivity to type I pyrethroids were seen (Sheets, 2000). Other investigators, however, have demonstrated that fetal or young rats and mice are sensitive to the neurochemical and neurobehavioral effects of pyrethroids (Aziz et al., 2001; Eriksson and Fredriksson, 1991; Husain et al., 1994; Lazarini et al., 2001).
Type I and type II pyrethroids exert their toxicity by affecting the voltage-gated sodium channels of neurons (Narahashi, 1996, 2001; Soderlund et al., 2002; Vijverberg and van den Bercken, 1990). Slowing of the kinetics of activation and inactivation of the gates of the sodium channel by the pyrethroids results in a prolonged opening of individual sodium channels from the normal few milliseconds to several hundred milliseconds by type I pyrethroids and as long as several seconds by type II pyrethroids.
Type I and type II pyrethroids produce the T syndrome and the CS syndrome, respectively (see “Experimental Data” for descriptions of symptoms). In both syndromes, sodium currents of whole cells are greatly prolonged, and this leads to an increase in the depolarizing after-potential or a membrane depolarization. In the T syndrome, type I pyrethroids increase and prolong the depolarizing after-potential and generate repetitive after-discharges. In the CS syndrome, type II pyrethroids generally cause membrane depolarization that evokes repetitive discharges. There is also evidence that type II pyrethroids block the chloride-ion channel of the γ-aminobutyric acid-receptor channel complex (Ecobichon, 2001). To increase the depolarizing after-potential to the threshold for inducing repetitive discharges, only about 1% of the sodium-channel population of rat brain