title: Dosimetric anchoring of in vivo and in vitro studies for perfluorooctanoate and perfluorooctanesulfonate.
abstract: In order to compare between in vivo toxicity studies, dosimetry is needed to translate study-specific dose regimens into dose metrics such as tissue concentration. These tissue concentrations may then be compared with in vitro bioactivity assays to perhaps identify mechanisms relevant to the lowest observed effect level (LOEL) dose group and the onset of the observed in vivo toxicity. Here, we examine the perfluorinated compounds (PFCs) perfluorooctanoate (PFOA) and perfluorooctanesulfonate (PFOS). We analyzed 9 in vivo toxicity studies for PFOA and 13 in vivo toxicity studies for PFOS. Both PFCs caused multiple effects in various test species, strains, and genders. We used a Bayesian pharmacokinetic (PK) modeling framework to incorporate data from 6 PFOA PK studies and 2 PFOS PK studies (conducted in 3 species) to predict dose metrics for the in vivo LOELs and no observed effect levels (NOELs). We estimated PK parameters for 11 combinations of chemical, species, strain, and gender. Despite divergent study designs and species-specific PK, for a given effect, we found that the predicted dose metrics corresponding to the LOELs (and NOELs where available) occur at similar concentrations. In vitro assay results for PFOA and PFOS from EPA's ToxCast project were then examined. We found that most in vitro bioactivity occurs at concentrations lower than the predicted concentrations for the in vivo LOELs and higher than the predicted concentrations for the in vivo NOELs (where available), for a variety of nonimmunological effects. These results indicate that given sufficient PK data, the in vivo LOELs dose regimens, but not necessarily the effects, could have been predicted from in vitro studies for these 2 PFCs.
authors.affiliation: * National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711;
authors.forename: John F
authors.initials: JF
authors.lastname: Wambaugh
authors.forename: R Woodrow
authors.initials: RW
authors.lastname: Setzer
authors.forename: Ann M
authors.initials: AM
authors.lastname: Pitruzzello
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: David M
authors.initials: DM
authors.lastname: Reif
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Kleinstreuer
authors.forename: Nina Ching Y
authors.initials: NC
authors.lastname: Wang
authors.forename: Nisha
authors.initials: N
authors.lastname: Sipes
authors.forename: Matthew
authors.initials: M
authors.lastname: Martin
authors.forename: Kaberi
authors.initials: K
authors.lastname: Das
authors.forename: Jamie C
authors.initials: JC
authors.lastname: DeWitt
authors.forename: Mark
authors.initials: M
authors.lastname: Strynar
authors.forename: Richard
authors.initials: R
authors.lastname: Judson
authors.forename: Keith A
authors.initials: KA
authors.lastname: Houck
authors.forename: Christopher
authors.initials: C
authors.lastname: Lau
mesh_terms: D017738:Alkanesulfonic Acids / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D002210:Caprylates / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005466:Fluorocarbons / Q000493:pharmacokinetics / Q000633:toxicity*; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D005466:Fluorocarbons; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid
keywords: Bayesian analysis; ToxCast; compartment model; in vitro-in vivo extrapolation.; perfluorooctanesulfonate; perfluorooctanesulfonic acid; perfluorooctanoate; perfluorooctanoic acid; pharmacokinetics; saturable resorption model; statistical analysis