title: Additivity of pyrethroid actions on sodium influx in cerebrocortical neurons in primary culture.
abstract: BACKGROUND
  Pyrethroid insecticides bind to voltage-gated sodium channels and modify their gating kinetics, thereby disrupting neuronal function. Although previous work has tested the additivity of pyrethroids in vivo, this has not been assessed directly at the primary molecular target using a functional measure.
  
  
  OBJECTIVE
  We investigated the potency and efficacy of 11 structurally diverse food-use pyrethroids to evoke sodium (Na+) influx in neurons and tested the hypothesis of dose additivity for a mixture of these same 11 compounds.
  
  
  METHODS
  We determined pyrethroid-induced increases in Na+ influx in primary cultures of cerebrocortical neurons using the Na+-sensitive dye sodium-binding benzofuran isophthalate (SBFI). Concentration-dependent responses for 11 pyrethroids were determined, and the response to dilutions of a mixture of all 11 compounds at an equimolar mixing ratio was assessed. Additivity was tested assuming a dose-additive model.
  
  
  RESULTS
  Seven pyrethroids produced concentration-dependent, tetrodotoxin-sensitive Na+ influx. The rank order of potency was deltamethrin > S-bioallethrin > β-cyfluthrin > λ-cyhalothrin > esfenvalerate > tefluthrin > fenpropathrin. Cypermethrin and bifenthrin produced modest increases in Na+ influx, whereas permethrin and resmethrin were inactive. When all 11 pyrethroids were present at an equimolar mixing ratio, their actions on Na+ influx were consistent with a dose-additive model.
  
  
  CONCLUSIONS
  These data provide in vitro relative potency and efficacy measurements for 7 pyrethroid compounds in intact mammalian neurons. Despite differences in individual compound potencies, we found the action of a mixture of all 11 pyrethroids to be additive when we used an appropriate statistical model. These results are consistent with a previous report of the additivity of pyrethroids in vivo.
authors.affiliation: Creighton University, School of Medicine, Department of Pharmacology, Omaha, Nebraska 68178, USA.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Cao
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Shafer
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Crofton
authors.forename: Chris
authors.initials: C
authors.lastname: Gennings
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Murray
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007306:Insecticides / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D051379:Mice; D019579:Neocortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry / Q000494:pharmacology*; D011722:Pyrethrins / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D007306:Insecticides; D009498:Neurotoxins; D011722:Pyrethrins; D015222:Sodium Channels; D012964:Sodium