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Mechanisms of Pyrethroid Neurotoxicity: Implications for Cumulative Risk Assessment

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Mechanisms of Pyrethroid Neurotoxicity: Implications for Cumulative Risk Assessment Toxicology 171 (2002) 3–59 www.elsevier.com/locate/toxicol View metadata, citation and similar papers at core.ac.uk brought to you by CORE Mechanisms of pyrethroid neurotoxicity: implications for provided by CiteSeerX cumulative risk assessment David M. Soderlund a,*, John M. Clark b, Larry P. Sheets c, Linda S. Mullin d, Vincent J. Piccirillo e, Dana Sargent f, James T. Stevens g, Myra L. Weiner h a Department of Entomology, New York State Agricultural Experiment Station, Cornell Uni6ersity, Gene6a, NY 14456, USA b Department of Entomology, Uni6ersity of Massachusetts, Amherst, MA 01003, USA c Bayer Corporation, 17745 South Metcalf A6enue, Stilwell, KS 66085, USA d DuPont Crop Protection, Stine-Haskell Research Center, P.O. Box 30, Newark, DE 19714, USA e VJP Consulting, Inc., 22636 Glenn Dri6e, Suite 304, Sterling, VA 20164, USA f A6entis CropScience, 2 T.W. Alexander Dri6e, P.O. Box 12014, Research Triangle Park, NC 27709, USA g Syngenta Crop Protection, Inc., 410 Swing Road, Greensboro, NC 27409, USA h FMC Corporation, P.O. Box 8, Princeton, NJ 08543, USA Received 25 September 2001; accepted 10 October 2001 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 * Corresponding author. Tel.: +1-315-787-2364; fax: +1-315-787-2326. E-mail address: [email protected] (D.M. Soderlund). 0300-483X/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0300-483X(01)00569-8 4 D.M. Soderlund et al. / Toxicology 171 (2002) 3–59 models based on combined actions at a single target are not appropriate to assess the risks of cumulative exposure to multiple pyrethroids. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: FQPA; Pyrethroids; Toxicity; Sodium channel; Calcium channel; Chloride channel; Common mechanism 1. Introduction detail and only as they relate to the principal emphasis of this review. This document is in- The Food Quality Protection Act (FQPA) of tended to serve as a contemporary review of the 1996 dramatically altered the regulation of pesti- state of the science in the field of pyrethroid cides in the United States. This Act, which neurotoxicology and to inform and aid the regula- amended both the Federal Insecticide, Fungicide tory review of pyrethroids under the common and Rodenticide Act and the Federal Food, Drug mechanism statute of the FQPA. and Cosmetics Act, requires the United States Environmental Protection Agency (EPA) to con- sider a number of factors relative to the toxicol- 2. Structures and insecticidal properties of ogy of pesticides, including the cumulative effects pyrethroids of exposure to pesticides having a ‘common mech- anism of toxicity’. The methods for identifying 2.1. What is a pyrethroid? pesticides having a common mechanism of toxic- ity, and the ramifications of such a determination, The term ‘pyrethroid’ is commonly used to are only now beginning to be clarified. designate a synthetic insecticide that is derived Pyrethroids are a class of synthetic insecticides structurally from the natural pyrethrins, the six that have been designed and optimized based on insecticidal constituents of pyrethrum extract the structures of the pyrethrins, the six insecticidal (Fig. 1). Decades of research and development by constituents of the natural insecticide pyrethrum the agrochemical industry and by government and (Elliott, 1995). Since the 1970s the pyrethroids academic research laboratories have resulted in a have been widely used to control insect pests in wide range of pyrethroid structures and a multi- agriculture and public health. By the mid-1990s, tude of uses in agricultural, veterinary, medical pyrethroid use had grown to represent 23% of the and household pest control. The development of U.S. dollar value of the world insecticide market, synthetic pyrethroid insecticides has involved an ranking second only to organophosphorus com- iterative process of structural modification and pounds among insecticide classes (Casida and biological evaluation, so that the array of present- Quistad, 1998). day commercial and experimental insecticides This paper reviews the data available from the identified as ‘pyrethroids’ includes compounds published literature and from unpublished studies that are several conceptual steps removed from by pyrethroid manufacturers on the toxicity and the pyrethrins. In this review, we focus specifically mechanisms of toxic action of the pyrethroids in on pyrethrum (Fig. 1) and the following synthetic mammals. Pyrethroids as a class are acute neuro- pyrethroid insecticides that are registered for use toxicants, although some individual compounds in the United States and many other parts have been associated with the production of toxic of the world, either as fully racemic mixtures, effects on other organ systems in long-term feed- mixtures of specified isomers, or single resolved ing studies. In the context of the implementation isomers (Fig. 2): allethrin (both bioallethrin and of the FQPA and the need to discern common S-bioallethrin), bifenthrin, cyfluthrin (including mechanisms of toxicity, this review therefore fo- beta-cyfluthrin), cyhalothrin (including lambda- cuses on the neurotoxic actions of pyrethroids in cyhalothrin), cypermethrin (including zeta- mammals. Other topics (e.g. insecticidal activity; cypermethrin), deltamethrin, fenpropathrin, fen- toxicokinetics and metabolism) are covered in less valerate (including esfenvalerate), permethrin, D.M. Soderlund et al. / Toxicology 171 (2002) 3–59 5 Fig. 1. Structures of the six natural pyrethrins. resmethrin, tefluthrin, tetramethrin, and covered by the sequential replacement of struc- tralomethrin. tural elements of the pyrethrins with novel structural moieties that were selected to conserve 2.1.1. De6elopment of synthetic pyrethroids the molecular shape and physical properties of the The discovery and development of synthetic template structure. Because the pyrethrins are es- pyrethroid insecticides has been the subject of ters of a cyclopropanecarboxylic acid and a cy- numerous reviews. The summary that follows is clopentenolone alcohol (Fig. 1), synthetic based primarily on a recent comprehensive review modifications typically held one of these major by Elliott (1995) and on earlier sources cited domains of the molecule constant while introduc- therein. ing new structural features in the other. Although The principal drawback of pyrethrum as an the early stages of this process made reference to insecticide is its instability in light and air, which the natural pyrethrins as templates, subsequent limits its effectiveness in crop protection and stages employed newly discovered synthetic other insect control contexts in which residual pyrethroids with desirable insecticidal activity, activity is essential. The development of synthetic stability, and other properties as the templates for pyrethroids is the result of efforts to modify the the further design of new compounds. structure of the natural pyrethrins (Fig. 1) in Both the historical development of pyrethroids order to increase photostability while retaining as an insecticide class and the structural diversity the potent and rapid insecticidal activity and rela- of pyrethroids are illustrated by the compounds tively low acute mammalian toxicity of currently registered for use in the United States pyrethrum. Most synthetic pyrethroids were dis- (Fig. 2). Allethrin, one of the earliest of synthetic 6 D.M. Soderlund et al. / Toxicology 171 (2002) 3–59 Fig. 2. Structures of synthetic pyrethroids registered
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