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Citation
Tags
HERO ID
1936108
Reference Type
Journal Article
Title
Application of an updated physiologically based pharmacokinetic model for chloroform to evaluate CYP2E1-mediated renal toxicity in rats and mice
Author(s)
Sasso, AF; Schlosser, PM; Kedderis, GL; Genter, MB; Snawder, JE; Li, Z; Rieth, S; Lipscomb, JC
Year
2013
Is Peer Reviewed?
Yes
Journal
Toxicological Sciences
ISSN:
1096-6080
EISSN:
1096-0929
Volume
131
Issue
2
Page Numbers
360-374
Language
English
PMID
23143927
DOI
10.1093/toxsci/kfs320
Web of Science Id
WOS:000314153100004
Abstract
Physiologically based pharmacokinetic (PBPK) models are tools for interpreting toxicological data and extrapolating observations across species and route of exposure. Chloroform (CHCl(3)) is a chemical for which there are PBPK models available in different species and multiple sites of toxicity. Because chloroform induces toxic effects in the liver and kidneys via production of reactive metabolites, proper characterization of metabolism in these tissues is essential for risk assessment. Although hepatic metabolism of chloroform is adequately described by these models, there is higher uncertainty for renal metabolism due to a lack of species-specific data and direct measurements of renal metabolism. Furthermore, models typically fail to account for regional differences in metabolic capacity within the kidney. Mischaracterization of renal metabolism may have a negligible effect on systemic chloroform levels, but it is anticipated to have a significant impact on the estimated site-specific production of reactive metabolites. In this article, rate parameters for chloroform metabolism in the kidney are revised for rats, mice, and humans. New in vitro data were collected in mice and humans for this purpose and are presented here. The revised PBPK model is used to interpret data of chloroform-induced kidney toxicity in rats and mice exposed via inhalation and drinking water. Benchmark dose (BMD) modeling is used to characterize the dose-response relationship of kidney toxicity markers as a function of PBPK-derived internal kidney dose. Applying the PBPK model, it was also possible to characterize the dose response for a recent data set of rats exposed via multiple routes simultaneously. Consistent BMD modeling results were observed regardless of species or route of exposure.
Tags
•
Chloroform 2018 Update
TITLE AND ABSTRACT REVIEW
Included Studies
FULL-TEXT REVIEW
Included
PBPK Model
•
Chloroform Combined (current)
Chloroform (original)
References: 2000-2018
WoS
PubMed
Chloroform (2018 update)
TITLE AND ABSTRACT REVIEW
Included Studies
FULL-TEXT REVIEW
Included
PBPK Model
Chloroform (current)
Literature Search: Jan 2009 - March 2017
PubMed
Literature Search: 2009-2017 Oct. Update
WoS
•
Chloroprene
•
Methanol (Non-Cancer)
Cited in Final (2013)
Cited in External Review Draft (2013)
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