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

Details

• Personal Author:
  Garner CE ; Liang S ; Yin L ; Yu X
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Laboratories Occupational Health Respiratory System Safety Solvents Toxicology
• Keywords:
  Author Keywords: 1-bromopropane Brominated Propanes Chemical Kinetics F344 Rats Gas Uptake Inhalation Inhalation Studies Laboratory Animals Pharmacodynamics Physiologically Based Pharmacokinetic Modeling
• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Georgia ; New Mexico ; OSHA Region 4 ; OSHA Region 6
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  23-36
• Volume:
  145
• Issue:
  1
• NIOSHTIC Number:
  nn:20047599
• Citation:
  Toxicol Sci 2015 May; 145(1):23-36
• Contact Point Address:
  Xiaozhong Yu, Department of Environmental Health Science, College of Public Health, University of Georgia, EHS Bldg., 150 Green Street, Athens, Georgia 30602
• Email:
  yuxz@uga.edu
• CAS Registry Number:
  1-Bromopropane (CAS RN 106-94-5)
• Federal Fiscal Year:
  2015
• Performing Organization:
  University of Georgia, Athens
• Peer Reviewed:
  True
• Start Date:
  20130901
• Source Full Name:
  Toxicological Sciences
• End Date:
  20160831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:cad1fb1125d0b9d88a8e8bc22bccba231745799e92ca172ef31f86dcbe5538ba9aa19e7844abcac0c4e5812431bba69e5f4732bb39700d7349af829b65db05df
• Download URL:
  https://stacks.cdc.gov/view/cdc/202614/cdc_202614_DS1.pdf
• File Type:
  [PDF - 3.20 MB ]