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Toxicol Sci. 2015 May;145(1):23-36. doi: 10.1093/toxsci/kfv018. Epub 2015 Jan 28.

Physiologically based pharmacokinetic modeling for 1-bromopropane in F344 rats using gas uptake inhalation experiments.

Author information

1
*Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, Georgia 30602.
2
*Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 and Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, Georgia 30602 yuxz@uga.edu.

Abstract

1-Bromopropane (1-BP) was introduced into the workplace as an alternative to ozone-depleting solvents and increasingly used in manufacturing industry. The potential exposure to 1-BP and the current reports of adverse effects associated with occupational exposure to high levels of 1-BP have increased the need to understand the mechanism of 1-BP toxicity in animal models as a mean of understanding risk in workers. Physiologically based pharmacokinetic (PBPK) model for 1-BP has been developed to examine 2 metabolic pathway assumptions for gas-uptake inhalation study. Based on previous gas-uptake experiments in the Fischer 344 rat, the PBPK model was developed by simulating the 1-BP concentration in a closed chamber. In the model, we tested the hypothesis that metabolism responsibilities were shared by the p450 CYP2E1 and glutathione (GSH) conjugation. The results showed that 2 metabolic pathways adequately simulated 1-BP closed chamber concentration. Furthermore, the above model was tested by simulating the gas-uptake data of the female rats pretreated with 1-aminobenzotrizole, a general P450 suicide inhibitor, or d,l-buthionine (S,R)-sulfoximine, an inhibitor of GSH synthesis, prior to exposure to 800 ppm 1-BP. The comparative investigation on the metabolic pathway of 1-BP through the PBPK modeling in both sexes provides critical information for understanding the role of p450 and GSH in the metabolism of 1-BP and eventually helps to quantitatively extrapolate current animal studies to human.

KEYWORDS:

1-bromopropane; F344 rats; gas uptake inhalation; physiologically based pharmacokinetic modeling

PMID:
25634537
PMCID:
PMC4492407
DOI:
10.1093/toxsci/kfv018
[Indexed for MEDLINE]
Free PMC Article

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