Comparative functional observational battery study of twelve commercial pyrethroid insecticides in male rats following acute oral exposure.

Twelve commercial pyrethroid insecticides (technical-grade active ingredients) were evaluated individually for acute neurobehavioral manifestations of toxicity under conditions suited to assist with determining whether they act by a common mechanism of toxicity. The pyrethroids that were tested reflect a diversity of structures, including six with an alpha-cyano phenoxybenzyl moiety (beta-cyfluthrin, lambda-cyhalothrin, cypermethrin, deltamethrin, esfenvalerate and fenpropathrin) and six without this moiety (bifenthrin, S-bioallethrin, permethrin, pyrethrins, resmethrin and tefluthrin). These chemicals also present a variety of behavioral effects, including ones that are historically classified as causing a T (tremor), CS (choreoathetosis with salivation) or intermediate syndrome of intoxication, and others that have not previously been classified. Each pyrethroid that was tested consisted of the complement of isomers that occur in commercial products--a key factor for relevance for environmental and human exposure and for comparisons, since the biological activity of the individual isomers can vary tremendously. Young-adult male Sprague-Dawley rats (10 per dose group) were administered a single dose of pyrethroid by oral gavage, in corn oil, at a volume of 5 ml/kg. Each was tested at a range of two or three dose levels, including a minimally toxic dose, to establish the more sensitive manifestations of toxicity, and a more toxic dose, to establish a more complete spectrum of neurobehavioral manifestations. Animals were evaluated using a functional observational battery (FOB) that was designed to characterize and distinguish effects classically associated with T or CS syndromes of intoxication. The FOB was performed when manifestations of toxicity were most apparent at the time of peak effect (2, 4, or 8 h post-dosing) by observers who were blinded to dose group assignment, thus avoiding possible bias. The results from this study indicate that some pyrethroids clearly exhibit the historic classification symptoms of the T and CS syndromes while others do so less obviously. Use of the statistical technique of Principal Component Analysis (PCA) further helped interpret the study findings, as described in the accompanying paper (Breckenridge et al., 2009). These results establish manifestations of neurotoxicity in vivo that can be used as weight of evidence to determine whether pyrethroid insecticides act through a common mechanism of toxicity in mammals. Based on a review of the FOB data, analyzed by PCA, and other published data, two common mechanism groups are proposed. Group 1 would include pyrethrins, bifenthrin, resmethrin, permethrin, S-bioallethrin and tefluthrin. Group 2 would include cypermethrin, deltamethrin, esfenvalerate, beta-cyfluthrin and lambda-cyhalothrin. Fenpropathrin exhibited features of both groups.