Investigation of Inter-Individual Genetic Variability with Physiologically-Based Pharmacokinetic Models and Monte Carlo Analysis
Abstract
Genetic variability continues to be a component of interest in assessing the expected impact of chemical exposures on human health. Until the advent of modern omics rapid assessment technologies, broad assessment of genetic variation on individualized outcomes was limited to single gene variants. This work enlists genetic information from the DMET Plus Array which contains comprehensive and accurate genotyping of specific polymorphisms involved in drug metabolism from the Coriell Personalized Medicine Collaborative. The expected impact of genetic variation in metabolic and transporter processes was assessed in relation to chemicals commonly encountered in the United States Air Force environment. Ten variants in Cytochrome P450, Family 2, Subfamily E, Polypeptide 1 (CYP2E1) were chosen for initial consideration given its in processing volatile organic chemicals. Measured CYP2E1 variation and its expected impact were then incorporated into analyses via a physiologically-based pharmacokinetic (PBPK) model to assess the likely influence on blood time course of isopropanol, acetone and toluene. The PBPK model simulations show that the predictions are influenced by incorporating information on genetic variants and would, therefore, impact predicted exposure estimates. Application of these genome-informed insights will allow a refined estimate of expected exposure response and potentially the prediction of personalized health outcomes.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2020
- Accession Number
- AD1109562
Entities
People
- Darrin K. Ott
- Heather A. Pangburn
- Jeffery M. Gearhart
- Joseph P. Jarvis
- Tammie R. Covington
Organizations
- Henry M. Jackson Foundation for the Advancement of Military Medicine