title: Environmentally relevant pyrethroid mixtures: A study on the correlation of blood and brain concentrations of a mixture of pyrethroid insecticides to motor activity in the rat.
abstract: Human exposure to multiple pyrethroid insecticides may occur because of their broad use on crops and for residential pest control. To address the potential health risk from co-exposure to pyrethroids, it is important to understand their disposition and toxicity in target organs such as the brain, and surrogates such as the blood when administered as a mixture. The objective of this study was to assess the correlation between blood and brain concentrations of pyrethroids and neurobehavioral effects in the rat following an acute oral administration of the pyrethroids as a mixture. Male Long-Evans rats were administered a mixture of β-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate and cis- and trans-permethrin in corn oil at seven dose levels. The pyrethroid with the highest percentage in the dosing solution was trans-permethrin (31% of total mixture dose) while deltamethrin and esfenvalerate had the lowest percentage (3%). Motor activity of the rats was then monitored for 1h. At 3.5h post-dosing, the animals were euthanized and blood and brain were collected. These tissues were extracted and analyzed for parent pyrethroid using HPLC-tandem mass spectrometry. Cypermethrin and cis-permethrin were the predominate pyrethroids detected in blood and brain, respectively, at all dosage levels. The relationship of total pyrethroid concentration between blood and brain was linear (r=0.93). The pyrethroids with the lowest fraction in blood were trans-permethrin and β-cyfluthrin and in brain were deltamethrin and esfenvalerate. The relationship between motor activity of the treated rats and summed pyrethroid blood and brain concentration was described using a sigmoidal Emax model with the Effective Concentration50 being more sensitive for brain than blood. The data suggests summed pyrethroid rat blood concentration could be used as a surrogate for brain concentration as an aid to study the neurotoxic effects of pyrethroids administered as a mixture under the conditions used in this study.
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, United States. Electronic address: hughes.michaelf@epa.gov.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Hughes
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, United States.
authors.forename: David G
authors.initials: DG
authors.lastname: Ross
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Research Triangle Park, NC, United States.
authors.forename: James M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Scollon
authors.affiliation: National Research Council, Research Triangle Park, NC, United States.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Wolansky
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, United States.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Crofton
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: DeVito
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004347:Drug Interactions; D007306:Insecticides / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D011722:Pyrethrins / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D007306:Insecticides; D011722:Pyrethrins
keywords: Dosimetry; Mixture; Neurotoxicity; Pesticide; Pyrethroid