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Tags
HERO ID
3449552
Reference Type
Journal Article
Title
Physiologically based pharmacokinetic model for ethyl tertiary-butyl ether and tertiary-butyl alcohol in rats: Contribution of binding to α2u-globulin in male rats and high-exposure nonlinear kinetics to toxicity and cancer outcomes
Author(s)
Borghoff, SJ; Ring, C; Banton, MI; Leavens, TL
Year
2016
Is Peer Reviewed?
Yes
Journal
Journal of Applied Toxicology
ISSN:
0260-437X
EISSN:
1099-1263
Volume
37
Issue
5
Page Numbers
621-640
Language
English
PMID
27885692
DOI
10.1002/jat.3412
Web of Science Id
WOS:000398184300011
Abstract
In cancer bioassays, inhalation, but not drinking water exposure to ethyl tertiary-butyl ether (ETBE), caused liver tumors in male rats, while tertiary-butyl alcohol (TBA), an ETBE metabolite, caused kidney tumors in male rats following exposure via drinking water. To understand the contribution of ETBE and TBA kinetics under varying exposure scenarios to these tumor responses, a physiologically based pharmacokinetic model was developed based on a previously published model for methyl tertiary-butyl ether, a structurally similar chemical, and verified against the literature and study report data. The model included ETBE and TBA binding to the male rat-specific protein α2u-globulin, which plays a role in the ETBE and TBA kidney response observed in male rats. Metabolism of ETBE and TBA was described as a single, saturable pathway in the liver. The model predicted similar kidney AUC0-∞ for TBA for various exposure scenarios from ETBE and TBA cancer bioassays, supporting a male-rat-specific mode of action for TBA-induced kidney tumors. The model also predicted nonlinear kinetics at ETBE inhalation exposure concentrations above ~2000 ppm, based on blood AUC0-∞ for ETBE and TBA. The shift from linear to nonlinear kinetics at exposure concentrations below the concentration associated with liver tumors in rats (5000 ppm) suggests the mode of action for liver tumors operates under nonlinear kinetics following chronic exposure and is not relevant for assessing human risk. Copyright © 2016 The Authors Journal of Applied Toxicology Published by John Wiley & Sons Ltd.
Tags
IRIS
•
tert-Butanol
Supporting Studies
Sources of Mechanistic and Toxicokinetic Data
PBPK/ADME
LitSearch: Jan 2017 - July 2019
PubMed
•
ETBE
Supporting Studies
Sources of Mechanistic and Toxicokinetic Data
PBPK/ADME
Cited in Document
LitSearch: Jan 2017 - July 2019
WoS
PubMed
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