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DOI10.1093/toxsci/kft204
Dosimetric Anchoring of In Vivo and In Vitro Studies for Perfluorooctanoate and Perfluorooctanesulfonate
Wambaugh, John F.1; Setzer, R. Woodrow1; Pitruzzello, Ann M.2; Liu, Jie1; Reif, David M.1; Kleinstreuer, Nicole C.1; Wang, Nina Ching Y.3; Sipes, Nisha1; Martin, Matthew1; Das, Kaberi4; DeWitt, Jamie C.5; Strynar, Mark6; Judson, Richard1; Houck, Keith A.1; Lau, Christopher4
发表日期2013-12-01
ISSN1096-6080
卷号136期号:2页码:308-327
英文摘要

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 EPAs 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.


英文关键词perfluorooctanoate;perfluorooctanoic acid;perfluorooctanesulfonate;perfluorooctanesulfonic acid;compartment model;saturable resorption model;pharmacokinetics;statistical analysis;Bayesian analysis;ToxCast;in vitro-in vivo extrapolation
语种英语
WOS记录号WOS:000328695500005
来源期刊TOXICOLOGICAL SCIENCES
来源机构美国环保署
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/59740
作者单位1.US EPA, Natl Ctr Computat Toxicol, Off Res & Dev, Res Triangle Pk, NC 27711 USA;
2.Res Triangle Inst, Res Triangle Pk, NC 27711 USA;
3.US EPA, Natl Ctr Environm Assessment, Off Res & Dev, Cincinnati, OH 45268 USA;
4.US EPA, Natl Hlth & Environm Effects Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA;
5.E Carolina Univ, Brody Sch Med, Dept Pharmacol & Toxicol, Greenville, NC 27834 USA;
6.US EPA, Natl Exposure Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA
推荐引用方式
GB/T 7714
Wambaugh, John F.,Setzer, R. Woodrow,Pitruzzello, Ann M.,et al. Dosimetric Anchoring of In Vivo and In Vitro Studies for Perfluorooctanoate and Perfluorooctanesulfonate[J]. 美国环保署,2013,136(2):308-327.
APA Wambaugh, John F..,Setzer, R. Woodrow.,Pitruzzello, Ann M..,Liu, Jie.,Reif, David M..,...&Lau, Christopher.(2013).Dosimetric Anchoring of In Vivo and In Vitro Studies for Perfluorooctanoate and Perfluorooctanesulfonate.TOXICOLOGICAL SCIENCES,136(2),308-327.
MLA Wambaugh, John F.,et al."Dosimetric Anchoring of In Vivo and In Vitro Studies for Perfluorooctanoate and Perfluorooctanesulfonate".TOXICOLOGICAL SCIENCES 136.2(2013):308-327.
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