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Event: 1353

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Inhibit, voltage-gated sodium channel

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Inhibit, voltage-gated sodium channel

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Molecular events lead to epilepsy KeyEvent Lyle Burgoon (send email) Open for adoption
presynaptic neuron 1 activation to epilepsy KeyEvent Lyle Burgoon (send email) Open for adoption
Inhibition of voltage gate during development is leading to cognitive disorders MolecularInitiatingEvent Andrea Terron (send email) Under development: Not open for comment. Do not cite


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Vertebrates Vertebrates NCBI
Invertebrates Invertebrates NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Ion channels are integral membrane proteins that are critical for neuronal function. They form pores in the plasma membrane that allow certain ions to travel with their concentration gradient across the membrane. Those that open in response to a change in membrane voltage potential are called voltage-gated ion channels. Channels that open in response to binding using a chemical signal or molecule are ligand-gated ion channels. In neurons, ion channels are essential for chemical communication between cells, or synaptic transmission. Ion channels also function to maintain membrane potential and initiate and propagate electrical impulses. Voltage-gated sodium channels are therefore responsible for action potential initiation and propagation in excitable cells, including nerve, muscle and neuroendocrine cell types. They are also expressed at low levels in non-excitable cells. It is important to note is that functional VGSC are present in both grey and white matter in the brain and approximately 50% of white matter oligodendrocyte precursor cells producing trains of action potentials and receiving synaptic input (Fields, 2008). VGSC are also present on microglia cells and contribute to release of major pro-inflammatory cytokines (Hossain et al., 2017).

Mammalian VGSC are composed of one α and two β subunits. Ten separate α subunits (Ogata and Ohishi, 2002) and four different β subunits (Isom, 2002) have been identified and are expressed in a tissue, region and time specific manner. The diverse functional roles of VGSCs depend on the numerous potential combinations of α and β subunits (Ogata and Ohishi, 2002). The type of VGSCs expressed in different cell types and regions, and their sensitivity and their functional role, may all contribute to the manifestation of toxicity and age dependent sensitivity, including the effects caused by pyrethroids.

At resting membrane potentials the channel is closed. During the rising phase of an action potential the channel activates or opens. Channel inactivation contributes to the falling phase. During the undershoot phase the channel deactivates before returning to the closed phase once resting membrane resting potential has been restored. Source: adapted from Motifolio Biomedical PowerPoint Toolkit Suite.

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

The sodium channel protein has been discovered and characterised in biochemical and molecular detail, even to atomic resolution. The initial works performed to measure and detect the electrical signals in nerves were initiated by Hodgkin and Huxley in 1952, showing a voltage‐dependent activation of sodium current that carries Na+ inward. The structure of VGSCs is nowadays known in detail and some seminal papers are available (Catterall, 2012).

Intracellular microelectrode recording using voltage or patch clamp are the common methods used for electrophysiological studies of VGSC. Channels and locations can also be measured using immunohistochemical methods, transcriptomics and at protein levels.

Expression of different sodium channel isoforms can be measured using a panel of sodium channel subunit-specific antibodies. Quantification of immunocytochemical staining is difficult due to differences in equipment, tissue preparation, inter-assay variability and analysis methods. However, using a quantitative approach, it is possible to determine the localisation and relative levels of sodium channel subunit protein expression (Westenbroek et al., 2013). PCR amplification and competitive PCR approach, real-time PCR, are used to isolate the mRNA levels of VGSC isoforms (Haufe et al., 2005).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Every cell within living organisms actively maintains an intracellular Na+ concentration that is 10–12 times lower than the extracellular concentration. The cells then utilise this transmembrane Na+ concentration gradient as a driving force to produce electrical signals, sometimes in the form of action potentials. The protein family comprising VGSC (Navs) is essential for such signalling and enables cells to change their status in a regenerative manner and to rapidly communicate with one another. VGSC were first predicted in squid and were later identified through molecular biology in the electric eel. Since then, these proteins have been discovered in organisms ranging from bacteria to humans (Chaihne, 2018).

Sodium channels consist of a highly processed α subunit, which is approximately 260 kDa, associated with auxiliary β subunits of 33–39 kDa. Sodium channels in the adult central nervous system (CNS) and heart contain a mixture of β1–β4 subunits, while sodium channels in adult skeletal muscle have only the β1 subunit. Nine different sodium channels have been identified using electrophysiological recording, biochemical purification, and cloning (Catterall, 2012).

Nomenclature of the different sodium channels utilises a numerical system to define subfamilies and subtypes based on similarities between the amino acid sequences of the channels. In this nomenclature system, the name of an individual channel consists of the chemical symbol of the principal permeating ion (Na) with the principal physiological regulator (voltage) indicated as a subscript (Nav). The number following the subscript indicates the gene subfamily (currently only Nav 1), and the number following the full point identifies the specific channel isoform (e.g. Na­v 1.1). This last number has been assigned according to the approximate order in which each gene was identified. Splice variants of each family member are identified by lower-case letters following the numbers (e.g. Nav 1.1a). Nine mammalian sodium channel isoforms have been identified and functionally expressed with all greater than 50% identical in amino acid sequence in the transmembrane and extracellular domains, where the amino acid sequence is similar enough for clear alignment (Catterall, 2012). In addition to these nine sodium channels that have been functionally expressed, closely related sodium channel-like proteins (Nax) have been cloned from mouse, rat and human. They are approximately 50% identical to the Nav 1 subfamily of channels but more than 80% identical to each other (Catterall, 2012).

In mammals, neuronal VGSC are expressed in the adult and developing brain. Evidence from mutation and knockout animal models demonstrates that perturbation of VGSC function during development impair nervous system structure and function, including muscle function, pain reception and cardia arrythmias (Chahine, 2018). VGSC show complex regional and temporal ontogeny in mammals (see Table 1, from Shafer et al., 2005). In general, embryonically expressed forms of VGSCs are replaced by expression of adult forms as neurodevelopment proceeds.

This complex ontogeny of VGSCs confounds any simple linkage of VGSCs to adverse outcomes and is an uncertainty in the development of this AOP. Since brain development in both humans and rodents extends from early gestation through lactation, it is not currently possible to state which VGSC subtype, or subtypes, may be responsible for the AOs.

Ion channels, including VGSCs, are also expressed in oligodendrocytes, Schwann cells (Baker, 2002) and microglia (Hossain et al., 2017). The expression and function of VGSS in cells of the oligodendrocyte lineage follow a time and regional ontogeny. While present and active in the early stages of oligodendrocyte maturation, VGSC function decreases over developmental time and is absent in mature oligodendrocytes (Paez et al., 2009; Berret et al., 2017). Knockdown of VGSC in rat oligodendrocyte precursor cells (OPCs) leads to reduced myelination suggesting a function of VGSC for axon myelination (Berret et al., 2017).

The physiological and anatomical ontogeny of Schwann cells is well known (Jessen and Mirsky, 2005). VGSCs are present in Schwann cells including the tetrodotoxin sensitive and Nav 1.7 types (Ritche, 1992; Chiu, 1991; Baker, 2002) less is known about their developmental profile.

Microglia cells express several ion channels, including Cl-, K+, H+ and Ca2+ and VGSC that are involved in several cellular functions such as maintaining the membrane potential, cellular volume and intracellular ion concentrations. VGSCs are demonstrated, to be present both in rodents and human microglia. Different isoforms are present in primary microglia (Nav 1.1, 1.2, 1.3, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.1 isoforms) compared to immortalised BV2 cells (Nav 1.2, 1.3, 1.4, 1.6, 1.8, 1.9, and 2.1 isoforms) (Jung et al., 2013; Black and Waxman, 2012; reviewed by Hossain et al., 2017). Presence of sodium channel isoforms in immortalised BV2 cells and primary microglia were detected by mRNA expression with standard PCR. BV2 cells express some sodium channel isoforms including Nav 1.2, 1.3, 1.4, 1.6, 1.8, 1.9, and 2.1 whereas primary microglia from 1–2-day-old mice express channel isoforms Nav 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7 1.8, 1.9, and 2.1. Primary microglia expressed higher levels of Nav 1.1. 1.2, 1.3, 1.6, 1.9, and 2.1 compared with BV2 cells.

Evidence for Perturbation by Stressor

Overview for Molecular Initiating Event

When a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to list stressors known to trigger the MIE and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). Depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). Known stressors should be included in the MIE description, but it is not expected to include a comprehensive list. Rather initially, stressors identified will be exemplary and the stressor list will be expanded over time. For more information on MIE, please see pages 32-33 in the User Handbook.

Due to their importance in neurons, sodium channels are known molecular targets of neurotoxins and neurotoxicants (Wakeling et al., 2012). There is strong evidence implicating the voltage-sensitive sodium channel as the principal site of insecticidal action of pyrethroids, which has led to extensive studies of the action of pyrethroids on mammalian sodium channels. Binding studies using radioactive pyrethroid demonstrated specific binding of the pyrethroid to rat brain VGSC α subunits (Trainer et al., 1997).

Pyrethrins and Pyrethroids

Natural toxins, produced by animal, plant and microorganisms, target VGSCs through diverse strategies developed over millions of years of evolution. The sodium transients can be antagonised by TTX (tetrodotoxin) (Káradóttir et al., 2008; Berrett et al., 2017) which is the classic stressor. Classic and well studied stressors for VGSCs are pyrethroid insecticides. Indeed, it is well known and accepted that pyrethroids bind to the α subunit of the neuronal VGSC (Trainer et al., 1997; Smith and Soderlund, 1998, 2001; Catterall et al., 2007; Cao et al., 2011). Mutations in the α subunit of both insects (Lee and Soderlund, 2001; Smith et al., 1997) and mammals (Vais et al., 2000, 2001; Wang et al., 2001) alter the sensitivity of VGSCs to pyrethroids, supporting the conclusion that pyrethroid interact with the α subunit (Shafer et al., 2005). The β subunit has been observed to modulate the affinity of pyrethroid interaction with the channel (Smith and Soderlund, 1998). However, the pyrethroid sensitivity of VGSCs subunits and splice variants expressed during development has yet to be examined (Shafer et al., 2005). The actions of pyrethroid insecticides on sodium channels in invertebrate and vertebrate nerve preparation have been widely documented over the past decades and has been extensively and critically summarised in numerous reviews (Soderlund et al., 2002; Chahine, 2018). Based on their chemical structure and clinical symptoms of toxicity, pyrethroids are classified in type I and type II. Following the binding to a VGSC specific isoform/s, pyrethroid slow the activation or opening, of VGSC. In addition, they slow the rate of VGSC inactivation (or closing) and shift to a more hyperpolarised potentials the membrane potentials at which VGSC activate (or open) (Narahashi, 1996). The result is that sodium channels open at more hyperpolarised potential and are held open longer, allowing more sodium ions to cross and depolarise the neuronal membrane. Type II pyrethroids delay the inactivation of VGSCs longer than do type I pyrethroids, leading to a depolarisation-dependent block. These differences in prolongation of channel open times are considered to contribute to the different toxicological profile (Ray 2001). See Figure 4 below from Shafer et al. (2005).

Figure 4: Pyrethroid effects on neuronal excitability

The figure summarises the pyrethroid effects on individual channels, whole-cell sodium currents and action potentials. Pyrethroid inhibit the function of two different ‘gates’ that control sodium flux through VGSC, delaying inactivation (indicated by the double arrow between states) of the channel and allowing continued sodium flux. Pyrethroid-mediated VGSC remain open when depolarisation ends, resulting in a ‘tail’ current. Type I pyrethroids action results in a series of action potentials, while type II pyrethroids cause greater membrane depolarisation, leading to a depolarisation-dependent block. Source: Shafer et al., 2005.


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help

Baker MD, 2002. Electrophysiology of mammalian Schwann cells. Progress in Biophysics and Molecular Biology, 78(2–3), 83–103.–6107(02)00007-X

Berret E, Barron T, Xu J, Debner E, Kim EJ and Kim JH, 2017. Oligodendroglial excitability mediated by glutamatergic inputs and Nav1.2 activation. Nature Communications, 8(1), 1–15.–017–00688–0

Black JA and Waxman SG, 2012. Sodium channels and microglial function. Experimental Neurology, 234(2), 302–315.

Cao Z, Shafer TJ and Murray TF, 2011. Mechanisms of pyrethroid insecticide-induced stimulation of calcium influx in neocortical neurons, Journal of Pharmacology and Experimental Therapeutics, 336 (1), 197–205. American Society for Pharmacology and Experimental Therapeutics. doi:

Catterall WA, 2012. Voltage‐gated sodium channels at 60: structure, function and pathophysiology. Journal of Physiology, 590(11), 2577–2589.

Catterall WA, Cestèle S, Yarov-Yarovoy V, Frank HY, Konoki K and Scheuer T, 2007. Voltage-gated ion channels and gating modifier toxins. Toxicon, 49(2), 124–141. doi: 10.1016/j.toxicon.2006.09.022

Chahine M (ed.), 2018. Voltage-gated Sodium Channels: Structure, Function and Channelopathies. Vol. 246. Springer.

Chiu SY, 1991. Functions and distribution of voltage‐gated sodium and potassium channels in mammalian Schwann cells. Glia, 4(6), 541–558.

Fields RD, 2008. Oligodendrocytes changing the rules: action potentials in glia and oligodendrocytes controlling action potentials. The Neuroscientist, 14(6), 540–543.

Haufe V, Camacho JA, Dumaine R, Günther B, Bollensdorff C, Von Banchet GS, and Zimmer, T, 2005. Expression pattern of neuronal and skeletal muscle voltage‐gated Na+ channels in the developing mouse heart. Journal of Physiology, 564(3), 683–696.

Hossain MM, Liu J and Richardson JR, 2017. Pyrethroid insecticides directly activate microglia through interaction with voltage-gated sodium channels. Toxicological Sciences, 155(1), 112–123. Oxford Academic,

Isom LL, 2002. β subunits: Players in neuronal hyperexcitability? Sodium Channels and Neuronal Hyperexcitability, 124, 124–138.

Jessen KR and Mirsky R, 2005. The origin and development of glial cells in peripheral nerves. Nature Reviews in Neuroscience, 6, 671–682.

Jung GY, Lee JY, Rhim H, Oh TH and Yune TY, 2013. An increase in voltage‐gated sodium channel current elicits microglial activation followed inflammatory responses in vitro and in vivo after spinal cord injury. Glia, 61(11), 1807–1821.

Káradóttir R, Hamilton NB, Bakiri Y and Attwell D, 2008. Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter. Nature Neuroscience, 11(4), 450–456.

Lee SH and Soderlund DM, 2001. The V410M mutation associated with pyrethroid resistance in Heliothis virescens reduces the pyrethroid sensitivity of house fly sodium channels expressed in Xenopus oocytes. Insect Biochemistry and Molecular Biology, 31(1), 19–29.–1748(00)00089-8

Narahashi T, 1996. Neuronal ion channels as the target sites of insecticides. Pharmacology and Toxicology, 79(1), 1–14.–0773.1996.tb00234.x

Ogata N and Ohishi Y, 2002. Molecular diversity of structure and function of the voltage-gated Na+ channels. Japanese Journal of Pharmacology, 88(4), 365–377.

Paez PM, Fulton D, Colwell CS and Campagnoni AT, 2009. Voltage‐operated Ca2+ and Na+ channels in the oligodendrocyte lineage. Journal of Neuroscience Research, 87(15), 3259–3266.

Ray DE, 2001. Pyrethroid insecticides: mechanisms of toxicity, systemic poisoning syndromes, paresthesia, and therapy. In: Krieger RI and Krieger WC. Handbook of Pesticide Toxicology. Academic Press, pp. 1289–1303.

Ritchie JM, 1992. Voltage-gated ion channels in Schwann cells and glia. Trends in Neurosciences, 15(9), 345–351.–2236(92)90052-A

Shafer TJ, Meyer DA and Crofton KM, 2005. Developmental neurotoxicity of pyrethroid insecticides: critical review and future research needs. Environmental Health Perspectives, 113(2), 123–136.

Smith TJ and Soderlund DM, 1998. Action of the pyrethroid insecticide cypermethrin on rat brain IIa sodium channels expressed in xenopus oocytes. Neurotoxicology, 19(6), 823–832.

Smith TJ and Soderlund DM, 2001. Potent actions of the pyrethroid insecticides cismethrin and cypermethrin on rat tetrodotoxin-resistant peripheral nerve (SNS/PN3) sodium channels expressed in Xenopus oocytes. Pesticide Biochemistry and Physiology, 70(1), 52–61.

Smith TJ, Lee SH, Ingles PJ, Knipple DC and Soderlund DM, 1997. The L1014F point mutation in the house fly Vssc1 sodium channel confers knockdown resistance to pyrethroids. Insect Biochemistry and Molecular Biology, 27(10), 807–812.–1748(97)00065–9

Soderlund DM, Clark JM, Sheets LP, Mullin LS, Piccirillo VJ, Sargent D, and Weiner ML, 2002. Mechanisms of pyrethroid neurotoxicity: implications for cumulative risk assessment. Toxicology, 171(1), 3–59.–483X(01)00569–8

Trainer VL, McPhee JC, Boutelet-Bochan H, Baker C, Scheuer T, Babin D, and Catterall WA, 1997. High affinity binding of pyrethroids to the α subunit of brain sodium channels. Molecular Pharmacology, 51(4), 651–657. doi:

Vais H, Williamson MS, Devonshire AL and Usherwood PNR, 2001. The molecular interactions of pyrethroid insecticides with insect and mammalian sodium channels. Pest Management Science, 57(10), 877–888.

Vais H, Williamson MS, Goodson SJ, Devonshire AL, Warmke JW, Usherwood PN and Cohen CJ, 2000. Activation of Drosophila sodium channels promotes modification by deltamethrin: reductions in affinity caused by knock-down resistance mutations. Journal of General Physiology, 115(3), 305–318. doi:

Volpe JJ, Kinney HC, Jensen FE and Rosenberg PA, 2011. Reprint of ‘The developing oligodendrocyte: key cellular target in brain injury in the premature infant’. International Journal of Developmental Neuroscience, 29(6), 565–582.

Wakeling EN, Neal AP and Atchison WD, 2012. Pyrethroids and their effects on ion channels. Pesticides—Advances in Chemical and Botanical Pesticides. Rijeka, Croatia: InTech, 39–66.

Wang SY, Barile M and Wang GK, 2001. A phenylalanine residue at segment D3-S6 in Nav1.4 voltage-gated Na+ channels is critical for pyrethroid action. Molecular Pharmacology, 60(3), 620–628.

Westenbroek RE, Bischoff S, Fu Y, Maier SK, Catterall WA and Scheuer T, 2013. Localization of sodium channel subtypes in mouse ventricular myocytes using quantitative immunocytochemistry. Journal of Molecular and Cellular Cardiology, 64, 69–78. doi: 10.1016/j.yjmcc.2013.08.004