Document rpLRQQ9d0xM9mGZDKmJn30w6r

AR226-3378 Abstract Perfluorooctanoic acid (PFOA) is a Fluoroorganic surfactant that has b production of a variety ofFluoropolymers. Considerable focus has be describing the bioexposure potential of PFOA because of a recent deci another Fluoroorganic compound, perfluorooctanyl sulfonate (PFOS), marketplace. In order to compare the bioexposure potential of PFOA rats were dosed once per day for 10 days and followed for 94 days. B and analyzed for total Fluorine on days 1, 5, 10, 13, 24, 52 and 94. No analysis of the blood data was conducted using a WinNonlin mathema package. There was considerable difference in PFOA and PFOS blood determined by peak blood concentrations and total exposure as determ under the curve (AUC) for doses normalized to 0.1 mmoles/Kg body w maximum concentration (Cmax) in blood was 518 and 990 uM equiva and PFOS, respectively. The PFOS AUC in blood was 8 times higher AUC based on a normalized dose of 0.1 mmol/Kg. The terminal half40.5 days for PFOS as compared to 8.3 days for PFOA. While PFOA both Fluoroofganic materials with surfactant properties, comparison o PFOS blood kinetics following repeated oral dosing illustrates that PF are kinetically different in the rat. f'SS:?^ Introduction t Perfluorooctanoic acid (PFOA) is a Fluoroorganic surfactant that has b production of a variety of Fluoropolymers. Considerable focus has be describing the bioexposure potential of PFOA because of a recent dec another Fluoroorganic compound, perfluorooctanyl sulfonate (PFOS), marketplace. In order to compare the bioexposure potential of PFOA rats were dosed once per day for 10 days and followed for 94 days. Bl analyzed for the total Fluorine content and used to compare the behavi PFOA in blood following oral dosing. ~vaV Materials and Methods Male Crl:CD(SD)IGS BR rats were used in this study. Rats were pu Charles River Laboratories, Inc., Raleigh, North Carolina and were ho stainless steel, wire-mesh cages suspended above cage boards. Anima maintained on an approximate 12-hour light/dark cycle (fluorescent lig temperature of 23 1C and a relative humidity of 50 10%. Tap wa ad libitum. All rats were fed PMI Nutrition International, Inc. Certifie LabDiet 5002 chow. PFOS and PFOA were provided as solid compo suspended as emulsions in their respective vehicles. Corn oil was use for PFOA. It was necessary to dissolve PFOS in acetone before suspe oil. The ratio of acetone to corn oil was 20:80. The dose volumes did 1 mL/100 g of body weight. The dosing suspensions were stirred on a plate throughout the dosing procedure to maintain homogeneity. Neg groups were used in this study. Corn oil and corn oiLacetone (80:20) the negative controls because they were the vehicles for the PFOA and respectively. Control rats were dosed in a room separate from the rats test substances. Approximately 2 hours after the first dose, 1-2 mL of collected into EDTA tubes from the orbital sinus of each rat. At all oth points, 5 rats/group were euthanized by carbon dioxide, and blood was days 5, 10, 13, 24, 52 and 94. Materials and Methods (contin t Five to 10 mL of blood was collected into EDTA tubes at sacrifice. Th rats was refrigerated until analyzed for total Fluorine. The total Fluorin blood samples was determined using a Wickbold torch combustion me by analysis with a Fluoride ion selective electrode. The liquid blood w or volatilized in the presence of wet oxygen and swept through an oxy in a closed quartz apparatus. The combustion products were collected absorbing solution and analyzed using a Fluoride ion selective electrod Noncompartmental analysis was conducted on blood fluorine data deri using WinNonlin Version 3.0 software (Pharsight Corp, Mountain Vie WinNonlin software provided a means of computing derived pharmac parameters from data files including area under the curve (AUC), Cma half-life (Tl/2). The AUC (concentration x time) represents the area u concentration curve from the time of dosing extrapolated to infinity. T included in determination of the terminal half-life were selected manu units of time. Since the dosages and fluorine content for each positive test material Varied, all doses were normalized to 0.1 mmol/kg for com purposes. The background was set at 0.2 ppm fluorine because of vari limited sensitivity of the analytical method. Since 0.2 ppm was the flu concentration limit of quantitation, any values listed as less than 0.2 pp from further treatment. Results The PFOS normalized pM equivalents in rat blood continued to rise t dosing period and may not have reached steady-state (Figure 1). The was 989.85 116.90 ppm (Mean SD) with a terminal half-life of 40 (Figure 2). The PFOA normalized jLiM equivalents in rat blood peake dosing and then decreased throughout the dosing period (Figure 3). T PFOA was 518.12 44.89 ppm (Mean SD) with a terminal half-life (Figure 4). For each of the test materials, blood was sampled at seven throughout the study; with only four of them occurring post-dose. Th size and analytical variability should be taken into account when usin terminal half-life for comparative purposes. The total internal exposu a normalized dose was described by AUC and was the basis for comp the test compounds. The AUC for the fluorine component was 566,47 for PFOS and PFOA, respectively (Figure 5). Figure 1 1200 JJ1000 (Q .^ 800 3 0- UJ 600 S 3 400 C g 200 S 0 0 pM Equivalents of PFOS in Rat Blood 10 20 30 40 50 60 70 8 Time (Days) Micromolar (jLim)Equivalents of PFOS in Male Rat Blood Resultin 10-day Oral Exposure to a Normalized Dose of 0.1 mmol/Kg. Valu Mean SD. Figure 2 Half-life Estimation Using pM Equivalents of PFOS Rat Bl 1000 JD (Q .Ss 3 UJ 100 0 00 (0 0 10 0 10 20 30 40 50 60 70 80 90 Time (Days) Half-life Estimation Using Micromolar (|Lim) Equivalents of PFOS Blood Resulting from a 10-day Oral Exposure to a Normalized Dos O.lmmol/Kg. Figure 3 |jM Equivalents of PFOA in Rat Blood Time (Days) Micromolar (jum) Equivalents of PFOA in Male Rat Blood Resultin 10-day Oral Exposure to a Normalized Dose of 0.1 mmol/Kg. Valu Mean SD. Figure 4 Half-life Estimation Using \M Equivalents of PFOA in 1000.0 -r 0 100.0 -^ c S 10.0 0 1.0 0.1 0 10 20 30 40 50 60 70 80 90 Time (Days) Half-life Estimation Using Micromolar (|Lim)Equivalents of PFOA Blood Resulting from a 10-day Oral Exposure to a Normalized Dos 0.1 mmol/Kg. 5 Comparison ofPFOS and PFOA AUCs in Male Rat Blood Resultin day Oral Exposure to a Normalized Dose of 0.1 mmol/Kg. Table 1 Comparison ofPFOS and PFOA Behavio Male Rat Blood Terminal Half-life (Days) Cmax(ppm) AUC Normalized Dose PFOS PF 4.05 989.8 566479.1 70 Conclusions 9 PFOS is absorbed at a faster rate and to a greater extent than PFOA PFOS is eliminated from the blood at a slower rate than PFOA For an equivalent dose, the Blood AUC is approximately 8x higher compared to PFOA.