title: Environmentally relevant mixing ratios in cumulative assessments: a study of the kinetics of pyrethroids and their ester cleavage metabolites in blood and brain; and the effect of a pyrethroid mixture on the motor activity of rats.
abstract: National surveys of United States households and child care centers have demonstrated that pyrethroids are widely distributed in indoor habited dwellings and this suggests that co-exposure to multiple pyrethroids occurs in nonoccupational settings. The purpose of this research was to use an environmentally relevant mixture of pyrethroids to assess their cumulative effect on motor activity and develop kinetic profiles for these pyrethroids and their hydrolytic metabolites in brain and blood of rats. Rats were dosed orally at one of two levels (1.5× or 5.0× the calculated dose that decreases rat motor activity by 30%) with a mixture of cypermethrin, deltamethrin, esfenvalerate, cis-/trans-permethrin, and β-cyfluthrin in corn oil. At 1, 2, 4, 8, or 24h after dosing, the motor activity of each animal was assessed and the animals sacrificed. Concentrations of pyrethroids in brain and blood, and the following metabolites: cis-/trans-dichlorovinyl-dimethylcyclopropane-carboxylic acid, 3-phenoxybenzoic acid, 3-phenoxybenzyl alcohol, 4-fluoro-3-phenoxybenzoic acid, and cis-dibromovinyl-dimethylcyclopropane-carboxylic acid were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS). Using this pyrethroid mixture in rats, the results suggest there is greater metabolism of trans-permethrin prior to entering the systemic circulatory system. All pyrethroids had tissue half-lives (t1/2) of less than 5h, excepting esfenvalerate in brain. At early time points, relative pyrethroid brain concentrations approximated their dose mixture proportions and a sigmoidal Emax model described the relationship between motor activity decrease and total pyrethroid brain concentration. In blood, the t1/2's of the cyclopropane metabolites were longer than the phenoxybenzoic metabolites. However, relative to their respective precursors, concentrations of the phenoxybenzoic acids were much higher than concentrations of the cyclopropane metabolites. Brain concentrations of all metabolites were low relative to blood concentrations. This implies limited metabolite penetration of the blood-brain barrier and little metabolite formation within the brain.
  
  
  CONCLUSIONS
  toxicokinetic differences between the pyrethroids did not appear to be important determinants of their relative potency and their effect on motor activity was consistent with a pyrethroid dose additive model.
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, United States. Electronic address: starr.james@epa.gov.
authors.forename: James M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: U.S. Environmental Protection Agency, Office of Air Quality Planning and Standards Health and Environmental Impacts Division, Research Triangle Park, NC 27711, United States.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Graham
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711, 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, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, United States.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Tornero-Velez
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Scollon
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Devito
authors.affiliation: U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711, 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 27711, 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 27711, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Hughes
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects; D006207:Half-Life; D007306:Insecticides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D008954:Models, Biological; D009043:Motor Activity / Q000187:drug effects*; D011722:Pyrethrins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D007306:Insecticides; D011722:Pyrethrins
keywords: Half-life; Pyrethroid metabolites; Pyrethroids; Toxicokinetics