Elsevier

Toxicology

Volume 171, Issue 1, 1 February 2002, Pages 3-59
Toxicology

Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment

https://doi.org/10.1016/S0300-483X(01)00569-8Get rights and content

Abstract

The Food Quality Protection Act (FQPA) of 1996 requires the United States Environmental Protection Agency to consider the cumulative effects of exposure to pesticides having a ‘common mechanism of toxicity.’ This paper reviews the information available on the acute neurotoxicity and mechanisms of toxic action of pyrethroid insecticides in mammals from the perspective of the ‘common mechanism’ statute of the FQPA. The principal effects of pyrethroids as a class are various signs of excitatory neurotoxicity. Historically, pyrethroids were grouped into two subclasses (Types I and II) based on chemical structure and the production of either the T (tremor) or CS (choreoathetosis with salivation) intoxication syndrome following intravenous or intracerebral administration to rodents. Although this classification system is widely employed, it has several shortcomings for the identification of common toxic effects. In particular, it does not reflect the diversity of intoxication signs found following oral administration of various pyrethroids. Pyrethroids act in vitro on a variety of putative biochemical and physiological target sites, four of which merit consideration as sites of toxic action. Voltage-sensitive sodium channels, the sites of insecticidal action, are also important target sites in mammals. Unlike insects, mammals have multiple sodium channel isoforms that vary in their biophysical and pharmacological properties, including their differential sensitivity to pyrethroids. Pyrethroids also act on some isoforms of voltage-sensitive calcium and chloride channels, and these effects may contribute to the toxicity of some compounds. Effects on peripheral-type benzodiazepine receptors are unlikely to be a principal cause of pyrethroid intoxication but may contribute to or enhance convulsions caused by actions at other target sites. In contrast, other putative target sites that have been identified in vitro do not appear to play a major role in pyrethroid intoxication. The diverse toxic actions and pharmacological effects of pyrethroids suggest that simple additivity models based on combined actions at a single target are not appropriate to assess the risks of cumulative exposure to multiple pyrethroids.

Introduction

The Food Quality Protection Act (FQPA) of 1996 dramatically altered the regulation of pesticides in the United States. This Act, which amended both the Federal Insecticide, Fungicide and Rodenticide Act and the Federal Food, Drug and Cosmetics Act, requires the United States Environmental Protection Agency (EPA) to consider a number of factors relative to the toxicology of pesticides, including the cumulative effects of exposure to pesticides having a ‘common mechanism of toxicity’. The methods for identifying pesticides having a common mechanism of toxicity, and the ramifications of such a determination, are only now beginning to be clarified.

Pyrethroids are a class of synthetic insecticides that have been designed and optimized based on the structures of the pyrethrins, the six insecticidal constituents of the natural insecticide pyrethrum (Elliott, 1995). Since the 1970s the pyrethroids have been widely used to control insect pests in agriculture and public health. By the mid-1990s, pyrethroid use had grown to represent 23% of the U.S. dollar value of the world insecticide market, ranking second only to organophosphorus compounds among insecticide classes (Casida and Quistad, 1998).

This paper reviews the data available from the published literature and from unpublished studies by pyrethroid manufacturers on the toxicity and mechanisms of toxic action of the pyrethroids in mammals. Pyrethroids as a class are acute neurotoxicants, although some individual compounds have been associated with the production of toxic effects on other organ systems in long-term feeding studies. In the context of the implementation of the FQPA and the need to discern common mechanisms of toxicity, this review therefore focuses on the neurotoxic actions of pyrethroids in mammals. Other topics (e.g. insecticidal activity; toxicokinetics and metabolism) are covered in less detail and only as they relate to the principal emphasis of this review. This document is intended to serve as a contemporary review of the state of the science in the field of pyrethroid neurotoxicology and to inform and aid the regulatory review of pyrethroids under the common mechanism statute of the FQPA.

Section snippets

What is a pyrethroid?

The term ‘pyrethroid’ is commonly used to designate a synthetic insecticide that is derived structurally from the natural pyrethrins, the six insecticidal constituents of pyrethrum extract (Fig. 1). Decades of research and development by the agrochemical industry and by government and academic research laboratories have resulted in a wide range of pyrethroid structures and a multitude of uses in agricultural, veterinary, medical and household pest control. The development of synthetic

Acute toxicity to mammals

Prior to 1970, there was little available information on the acute toxicity to mammals of the natural pyrethrins or the limited group of synthetic pyrethroids known at that time. The first systematic study of pyrethroid toxicity (Verschoyle and Barnes, 1972) compared the acute oral and intravenous toxicities to rats of pyrethrum, pyrethrin I, pyrethrin II, bioallethrin, isomers and isomer mixtures of resmethrin, and a structural relative of resmethrin. This study documented the modest oral

Physiological and neurochemical indices of intoxication

Administration of pyrethroids at doses that cause overt signs of acute intoxication produces a variety of effects that are detected using physiological and biochemical assays. The neurophysiological, neurochemical, and cardiovascular effects associated with acute pyrethroid intoxication are summarized in the following sections.

Pyrethroid toxicity

Most pyrethroids are moderately toxic (EPA Category II) to mammals. The principal effects observed following acute or subchronic exposure of mammals to pyrethroids as a class are various signs of excitatory neurotoxicity. In contrast, there is no evidence that other effects of pyrethroids, involving either acute effects on other organ systems or chronic effects, are characteristic of pyrethroids as a class (Clark, 1995). Therefore, consideration of common mechanisms among pyrethroids is

Acknowledgements

The preparation of this review was supported by the Pyrethroid Working Group, a consortium of firms (Aventis CropScience, Bayer Corporation, DuPont Crop Protection, FMC Corporation, Syngenta Crop Protection, Inc., and Valent Corporation) that market pyrethroid-based insecticide products in the United States. We thank the following persons for their contributions during the preparation of this review: Terry Fico (formerly of FMC Corporation); Joel Kronenberg (formerly of AgrEvo USA Company);

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