Dosimetric Anchoring of In Vivo and In Vitro Studies for Perfluorooctanoate and Perfluorooctanesulfonate
Autor: | Matthew T. Martin, Keith A. Houck, Jamie C. DeWitt, R. Woodrow Setzer, Ann Pitruzzello, Christopher Lau, Mark J. Strynar, John F. Wambaugh, Jie Liu, Kaberi P. Das, Richard S. Judson, Nicole Kleinstreuer, David M. Reif, Nisha S. Sipes, Nina Ching Y. Wang |
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Rok vydání: | 2013 |
Předmět: |
Male
Fluorocarbons Perfluorooctanesulfonic acid Dose-Response Relationship Drug Chemistry PK Parameters In Vitro Techniques Pharmacology Toxicology In vitro Rats Mice Inbred C57BL Rats Sprague-Dawley Macaca fascicularis Mice chemistry.chemical_compound Alkanesulfonic Acids Pharmacokinetics In vivo No-Observed-Effect Levels Dose group Animals Perfluorooctanoic acid Female Caprylates |
Zdroj: | Toxicological Sciences. 136:308-327 |
ISSN: | 1096-0929 1096-6080 |
Popis: | 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. |
Databáze: | OpenAIRE |
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