- Full (HTML) - Full (PDF) - Related EHP Articles - PubMed:Related Articles - PubMed:Citation - Cited in PMC - Purchase This Issue

Timothy J. Shafer,¹ Douglas A. Meyer,² and Kevin M. Crofton^1,2

¹Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA; ²Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Abstract
Pyrethroid insecticides have been used for more than 40 years and account for 25% of the worldwide insecticide market. Although their acute neurotoxicity to adults has been well characterized, information regarding the potential developmental neurotoxicity of this class of compounds is limited. There is a large age dependence to the acute toxicity of pyrethroids in which neonatal rats are at least an order of magnitude more sensitive than adults to two pyrethroids. There is no information on age-dependent toxicity for most pyrethroids. In the present review we examine the scientific data related to potential for age-dependent and developmental neurotoxicity of pyrethroids. As a basis for understanding this neurotoxicity, we discuss the heterogeneity and ontogeny of voltage-sensitive sodium channels, a primary neuronal target of pyrethroids. We also summarize 22 studies of the developmental neurotoxicity of pyrethroids and review the strengths and limitations of these studies. These studies examined numerous end points, with changes in motor activity and muscarinic acetylcholine receptor density the most common. Many of the developmental neurotoxicity studies suffer from inadequate study design, problematic statistical analyses, use of formulated products, and/or inadequate controls. These factors confound interpretation of results. To better understand the potential for developmental exposure to pyrethroids to cause neurotoxicity, additional, well-designed and well-executed developmental neurotoxicity studies are needed. These studies should employ state-of-the-science methods to promote a greater understanding of the mode of action of pyrethroids in the developing nervous system. Key words: age-dependent toxicity, biologically based dose-response model, developmental neurotoxicity, mode of action, physiologically based pharmacokinetic model, pyrethroid, risk assessment, voltage-sensitive sodium channel. Environ Health Perspect 113:123-136 (2005) . doi:10.1289/ehp.7254 available via http://dx.doi.org/ [Online 14 October 2004]

Address correspondence to T.J. Shafer, Neurotoxicology Division, MD B105-05, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 USA. Telephone: (919) 541-0647. Fax: (919) 541-4849. E-mail: shafer.tim@epa.gov

We thank D. Ray (Medical Research Council, UK) and Bayer CropScience for graciously making available unpublished data for this review ; L. Sheets (Bayer CropScience) and S. Padilla (U.S. EPA) for comments on a previous version of the manuscript ; and J. Harrill (University of North Carolina at Chapel Hill) and J. Havel (CSC Corporation) for their assistance with figures and graphics.

Preparation of this document has been funded wholly by the U.S. Environmental Protection Agency. This document has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

The authors declare they have no competing financial interests.

Received 14 May 2004 ; accepted 14 October 2004.