Critical Consideration of the Multiplicity of Experimental and Organismic Determinants of Pyrethroid Neurotoxicity: A Proof of Concept

Abstract

Pyrethroids (PYR) are pesticides with high insecticidal activity that may disrupt neuronal excitability in target and nontarget species. The accumulated evidence consistently showed that this neurophysiologic action is followed by alterations in motor, sensorimotor, neuromuscular, and thermoregulatory responses. Nevertheless, there are some equivocal results regarding the potency of PYR in lab animals. The estimation of potency is an important step in pesticide chemical risk assessment. In order to identify the variables influencing neurobehavioral findings across PYR studies, evidence on experimental and organismic determinants of acute PYR-induced neurotoxicity was reviewed in rodents. A comprehensive analysis of these studies was conducted focusing on test material and dosing conditions, testing conditions, animal models, and other determinants such as testing room temperature. Variations in the severity of the neurotoxicity, under lab-controlled conditions, was explained based upon factors including influence of animal species and age, test material features such as chemical structure and stereochemistry, and dosing conditions such as vehicle, route of exposure, and dose volume. If not controlled, the interplay of these factors may lead to large variance in potency estimation. This review examined the scope of acute toxicological data required to determine the safety of pesticide products, and factors and covariates that need to be controlled in order to ensure that predictivity and precaution are balanced in a risk assessment process within a reasonable time-frame, using acute PYR-induced neurotoxicity in rodents as an exemplar.

Acknowledgments

The U.S. Environmental Protection Agency through its Office of Research and Development reviewed and approved this publication. However, it may not necessarily reflect official agency policy, and reference to commercial products or services does not constitute endorsement. The authors express their gratitude to Drs. Anna B. Lowitt, Michael F. Hughes, and Elin Ulrich for their comments on an earlier version of this article, and Dr. Kevin M. Crofton for his kind and highly valued guidance before and during the construction of this work.