Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs

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.

Figure 1. Structures of pyrethroids for which developmental neurotoxicity has been examined. Developmental neurotoxicity studies have been conducted using either technical compound or formulations of the seven pyrethroids illustrated; the numbers in parentheses after each compound name indicate the number of studies that have been conducted using that compound or a formulation containing that compound. Only one stereoisomer is illustrated for each compound.

Figure 2. Eight possible stereoisomers of allethrin (A–H). The inset lists allethrin-containing products and the stereoisomer content of each.

Figure 3. Pyrethroid effects on neuronal excitability. This schematic depicts pyrethroid effects on individual channels, whole-cell sodium currents, and action potentials. Depolarization opens VSSCs (top left) allowing sodium to enter the cell. To limit sodium entry and depolarization length, VSSCs inactivate and must return to a “resting” state before reopening. Pyrethroids inhibit the function of two different “gates” that control sodium flux through VSSCs (top right), delaying inactivation (indicated by double arrows between states) of the channel and allowing continued sodium flux (Open*). If sodium current through an entire cell is measured, depolarization leads to a rapidly inactivating current under normal circumstances (bottom left, Sodium current). Pyrethroid-modified VSSCs remain open when depolarization ends (bottom right, Sodium current), resulting in a “tail” current (the notch at the end of example currents). If membrane voltage is examined, depolarization under normal circumstances generates a single action potential (bottom left). VSSCs modified by type I compounds (bottom right, Action potential) depolarize the cell membrane above the threshold for action potential generation, resulting in a series of action potentials (repetitive firing). Type II compounds cause greater membrane depolarization, diminishing the sodium electrochemical gradient and subsequent action potential amplitude. Eventually, membrane potential becomes depolarized above the threshold for action potential generation (depolarization-dependent block).

Figure 4. Major elements in a proposed BBDR model for pyrethroid neurotoxicity and research needs for the PBPK and PBPD components. Boxes with question marks indicate that the sequence of events between changes in the target and adverse effects has not been completely elucidated.