Document 4aqpJnKq7147gyz58vXnzaYOp

AR226-3379 Development Of A Biologically Based Model To Describe Perfluoroocta (PFOA) Kinetics P.M. Hinderliter, and G.W. Jepson The DuPont Company, Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware, USA Hjj Introduction Perduorooclanoic acid (PFOA) is a fluoroorganic surlaclant used in fluoropolymer processes. PFOA is reported to be melabolically inert. PFOA is abelieved lo be relatively biopersiaierit In humans. The receni removal ol perfluoroocianyl sullonale (PFOS) (rom Ihe marketplace has brought attention to other Iluoroorganic compounds Uver efiecis including peroxisome ptoliieralion have been noted in rats. Sex differences have been shown in the rat, PFOA Is cleared more rapidly in (he lemale rat lhan in the male raiSpecies differences have also been observed with the rat reportedly clearing PFOA more rapidly lhan the human. PfOteir> binding has been reported in the raL Target organs and proleins are not yet clearly idenlilied, Preliminary modeling eflons are based on available lileralura data. Perfiuorinaled Compounds: Sletic hindrance by large fluorine C-F bonds lonns a spiral sinjdure in the carbon chain and causes a more rigid molecule than in hydrocarbons. Fluorine Is highly electronegative and ihe caibon backbone is completely covered by the 'eleciron cloud' of fluorine atoms presenting an even charge dislribulion. C-F bonds are very sirong and short. | Materials and Methods All models were conslmcted using Advanced Continuous Simulation Language (ACSL). Tha preliminary models were tested against available laboratory and worker exposure dala for accaptahiliiyThe inlllal model was a non -physiological, 2-compartmenl model (Rgure 2). The lung and dermal compartments are included to accommodate potential exposure via ihese routes, but the primary focus o! the wsik is on the oral route of While Ihe liver is not a site of PFOA metabolism, it is described as a separate model compartment since it is a reported lonicily targel in some animal species and may represent a source ol significant protein binding. Physiological and chemical specific dala input into the model are shown in Table 1. Blood data compared againsi model simulations In Figures 4 and 5 were obtained from Ihe iilerature. | Table 1 - Input Parameters PBod.yBW.BIB_" _______BVW(WKB,) B.1..HumML 450 W S" ara""^,-- MchSBts ConElflnl KM SimorL) | Figure 2 - Two-Compartment Model Body lumped into single storage compartment f Figure 3 - PBPK Model | Figure 1 - Modeling Pathway (Figure 4 - Two-Compartment Results Stood dala Internals rala following a single gavage dosa [ Figure 5 -PBPK Results sd data in female rule [nilowiiig a single garage dose I Discussion The two-compartment model simulates Ihe general trends in the ral data. It is nol satisfactory, however. !or predictive uses. The preliminary PBPK model performs bailer than Ihe iwocamparlmeni model, but includes many estimated or lit' parameter values. One function of this investigation was to identify the dala gaps in the existing literature. Table 2 lists the relevant areas and their relative importanca lo the modeling eflort. The human data in the literature at this time are not complete enough !or modeling purposes. Mosi of Ihe human data are taken from monitoring of production workers and ihereby lacks any exposure information. In addition, there is no associated 'event' on which to base a lime scale. Tiie reported human blood concentrations ol PFOA are generally below 35 ppm. While prolein binding has been notetf in the literature, there is no information available to quantify the binding parameters. A binding term is included in the preliminary PBPK mode! but the values used have no physical significance at ihis point. (Table 2 - _d B*il<Jttz9RnpJ| Hi f Protein B Qualitative Binding Delerr Determine key tissues Identify targe! protein Delecmine branched Chech tonne presenc Quantitalion of Model Para Calculala stability, sto interaction with applic Determine differences PFOA. | Conclus Classical compartmsnta kinetics in mammalian s A preliminary rat PBPK Dala gaps were identifi development prase nted. Future Directions: Conduci Mass Balance studies in male and lem Characterize the rate, e human systems, Davelop model descript Include quantitative pro models. Use model to simulate elimination of PFOA in h