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Application of an updated physiologically-based pharmacokinetic model for chloroform to evaluate CYP2E1-mediated renal toxicity in rats and mice.

Authors
Sasso-AF; Schlosser-PM; Kedderis-GL; Genter-MB; Snawder-J; Li-Z; Rieth-S; Lipscomb-JC
Source
Toxicol Sci 2013 Feb; 131(2):360-374
NIOSHTIC No.
20041978
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. Since 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. While 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 paper, 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 dataset of rats exposed via multiple routes simultaneously. Consistent BMD modeling results were observed regardless of species or route of exposure.
Keywords
Pharmacodynamics; Physiological-chemistry; Physiological-factors; Physiological-testing; Laboratory-animals; Laboratory-testing; Chemical-kinetics; Chloromethanes; Methanes; Toxic-effects; Toxicology; Analytical-models; Analytical-processes; Renal-toxicity; Kidneys; Metabolic-rate; Metabolism; In-vitro-study; Humans; Metabolites; Drinking-water; Dose-response; Author Keywords: PBPK; chloroform; kidney; renal toxicity; model
Contact
A. F. Sasso, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, 1200 Pennsylvania Avenue, NW, Washington, DC 20460, USA
CODEN
TOSCF2
CAS No.
67-66-3
Publication Date
20130201
Document Type
Journal Article
Email Address
sasso.alan@epa.gov
Fiscal Year
2013
NTIS Accession No.
NTIS Price
Identifying No.
B20130124
Issue of Publication
2
ISSN
1096-6080
NIOSH Division
DART
Priority Area
Construction; Transportation, Warehousing and Utilities
Source Name
Toxicological Sciences
State
DC; NC; OH
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