Evidence for dose-additive effects of pyrethroids on motor activity in rats

Abstract

Background: Pyrethroids are neurotoxic insecticides used in a variety of indoor and outdoor applications. Previous research characterized the acute dose-effect functions for 11 pyrethroids administered orally in corn oil (1 mL/kg) based on assessment of motor activity.

Objectives: We used a mixture of these 11 pyrethroids and the same testing paradigm used in single-compound assays to test the hypothesis that cumulative neurotoxic effects of pyrethroid mixtures can be predicted using the default dose-addition theory.

Methods: Mixing ratios of the 11 pyrethroids in the tested mixture were based on the ED30 (effective dose that produces a 30% decrease in response) of the individual chemical (i.e., the mixture comprised equipotent amounts of each pyrethroid). The highest concentration of each individual chemical in the mixture was less than the threshold for inducing behavioral effects. Adult male rats received acute oral exposure to corn oil (control) or dilutions of the stock mixture solution. The mixture of 11 pyrethroids was administered either simultaneously (2 hr before testing) or after a sequence based on times of peak effect for the individual chemicals (4, 2, and 1 hr before testing). A threshold additivity model was fit to the single-chemical data to predict the theoretical dose-effect relationship for the mixture under the assumption of dose additivity.

Results: When subthreshold doses of individual chemicals were combined in the mixtures, we found significant dose-related decreases in motor activity. Further, we found no departure from the predicted dose-additive curve regardless of the mixture dosing protocol used.

Conclusion: In this article we present the first in vivo evidence on pyrethroid cumulative effects supporting the default assumption of dose addition.

Keywords: additivity; cumulative; mixtures; neurotoxicity; pyrethroids.

Figure 1

Time course of cumulative effects of 11 pyrethroids on figure-eight maze activity (mean ± SE). The arrow indicates the time of peak effects for the tested mixture.

Figure 2

Observed data (individual data points) and the model-predicted dose–response curve from the additivity threshold model given in Equation 2a for each of the 11 pyrethroids.

Figure 3

Dose–response relationships for the cumulative effects of 11 pyrethroids on figure-eight maze activity (mean ± SD). (A) SLT group. (B) SQT group. The departure of the experimental data from the predictive curve modeled assuming dose addition was not significant.