Document v6y8zV3aEOq3wy566G9M1ew7b

Development of a Mammalian Screen to Evaluate Absorption and Persistence of Fluorina C Finlay, G. Jepson, G. Kennedy, andJ. Stadler The DuPont Company, Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware, USA AR226-3386 ^Abstract uplalieaiitl clearance fora series of fiuoroorganii: chemicals, Eighteen chemicals were screened ai doses expected to be minmiaily tonic. Each cliemical was administered by oral gange to groups of 5 nils cadi for 10 days. Blood was collected 2 hours after [tie lirst cose. ami on days 5, 10 (treatment), 13.24,52, and 94 (posi-ireaiment). The toial fluorine content (ppin F) ill blood was determined by using a Wickboid lorcli combusiion/fluoride ion electrode analysis method. Noncoinpanmental analysis was conducted on blood fluorine data. The dose-normalized area under (lie blood-concenlration curve (AUOD) was calculated for eacli chemical and used as a comparalivc metric. The blood AUC/D for the cliemicals tested ranged from 566.500 for perfluoroociaiie sulfonate (PFOS) and 70,800 for pcrfluorooctanoic aciij (PFOA) to a range ofO 10 28,900 for a scries ofTelomer-based cliemicals. This screen could also tic used to assess [eveis of lest material derived fluorine in large! organs or estimate the hiologicalhalf-lifc of test materials. As utilized here, the screen cliemicals. I Introduction The objective of these studies was to examine the poietltial of selected fluorillflted organic chemicals 10 lie absorbed and persist in a mammalian system. Tilis rat assay was developed during a 10-day dosinE phase and an 84-day recovery phase were analyzed for total fluorine. The data were normalized so that comparisons could be nude, regardless of chemical characteristics or the dose administered- Non-comparttnentai kinetic analysis of t]ie blood daia was used to provide (he basis for comparisons. Liver samples were also analyzed for loial fluorine 10 supplenieni Hie information obtained from blood analyses. HH Methods - Animals - Sprague Dawley male rats Test Materials and Dosages - Selected liuorinmcd organic themicals were given 10 rats by gnvage at Ihe indicated weigh! gain) or an upper limit of 1000 mgAg/day. Perflurooctane sulfonale FluoroalkyleHlyl Sulfonate Fluomalkylclliyl Beiaine Fluoroalkyletltanol Mixture Fluoioalkylethyl Carboxylale Mixture ofFluoroaikyleihyl Anionic Surfaci 2-Perfluorooctyieiiumo I Fluoroalkylethyl Ethoxylale Fluoroalhycthyl Meihacrylate Polymer Fluoroalkylethyl Phosphate til Fhioioalkylethyl Phosphate ff2 Fluoroalkylethyl Urethane Polymer Polytetrafluoroethylenc Polyletrafluoroethylene mixture Periluoiopoiyedier fli Perfluoiopolyeiber lf2 Vehicles and Negative Controls - The lest chemicals were administered as received or were suspended in water, cora oil, or a mixture of acetone and corn oil (20:80). Negative control rals were1 dosed with waieror respective carriers. Study Design Total Fluorine Analyses - Wickboid torch combustion followed by analysis with selective ion electrode Data analyses - All data were normalized to 0.1 inmolc/kg based on dosage, percentage active The following pananeiers were calculated for the blood: AUCJNF/D (area under the curvel - Represents the area lamer tile blood concentratioc curve from [lie time of initial dosing extrapolated 10 infinity. Cmnx - Maximum observed concentralion in (he blood fSBlResults Magnitude of Response Comparisons - A plot of loial organic blood fluorine concentration normalized to microroolar equivalents vs. lime provides a comparison of the magnitude of Cmax and area under the carve fur selected cticmicals, iintiiscnample, four selected chemicals arc shown: * Comparison of AUCINF/0 for Blood Organic Fluorine Across Tested Chemicals Tlie area under die curve calculation provides an estimate of iota! fluorine load in the rat during the course of the dosing and recovery periods. Fourteen of the tested 18 chemicals are compared for relative accumulation in a rnanunalian system The oilier four chemicals tested had no measurable area under the curve. Determination of Uptake and Clearance - A plot ofblood fluorine levels vs. time illustrates Ihe rale of absorption and clearance chemicals are compared. Fluorine blood levels for Chemical F iio nol reach steady siale within the 10-day dosing period in this test No estimate of steady state level is available. Alternatively, tola) fluorine levels for Clieniical E indicate that the chemical may be approaclung steady state near tlie end of the dosing phase. Differences la clearance pauems can aiso be seen, initial clearance of Chemical F from the blood is rapid after dosing ceases and is followed by slower clearance between days 13 and Iln; end of the recovery pilasc. Clearance o f Chemical E Comparison of Organic Fluorine Levels in Blood and Liver Tile Wicfcbold torch can be used for combustion and subsequent analysisof total organic fluorine in tissue samples. In tlie first example, fluorine levels in blood and liver of animals treated with Chemicals AandB are compared at tlie end of dosing (Day 10), three days niter ihe dosing pliase (Day 13) and mine end of tile recovery phase (Day 94>. Both blood and liver samples tiave higher levels of organic flaorine in rals treated wilh Chemical A than in those treaied wiihB. - In the second example <Day 10) and at ilie en but levels of fluorine organic fluorine conteni of diffcrcul test materials. Ki ChejiiicalA(PFOS)ioalo values of 38,900 or less in Tlius, the calculated numb Todetermine if organic flu thai blood levels do not ac liverlevclswereevideDt.m of these inaieriais. Tlie Wi specific analytical method evaluaiinE the results of ex f Conclusio chemicals for bioaccumulatio the curve for perfluorooclane perfluoroocianoale (APFO) screen has [lie potential to be research and in development f Acknowle Tlie authors would like to tli Sludy technicians - Nila Baker, Rich Math Finorine analysis - Chris Bowers and Wa Kinetic analyses - Paul Hinderiitcr Poster Preparation - Maryanne Wilford