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Stochasticity in physiologically based kinetics models: implications for cancer risk assessment.

Authors
  • Péry, Alexandre Roger Raymond1
  • Bois, Frederic Yves
Type
Published Article
Journal
Risk analysis : an official publication of the Society for Risk Analysis
Publication Date
Aug 01, 2009
Volume
29
Issue
8
Pages
1182–1191
Identifiers
DOI: 10.1111/j.1539-6924.2009.01242.x
PMID: 19508449
Source
Medline
Language
English
License
Unknown

Abstract

In case of low-dose exposure to a substance, its concentration in cells is likely to be stochastic. Assessing the consequences of this stochasticity in toxicological risk assessment requires the coupling of macroscopic dynamics models describing whole-body kinetics with microscopic tools designed to simulate stochasticity. In this article, we propose an approach to approximate stochastic cell concentration of butadiene in the cells of diverse organs. We adapted the dynamics equations of a physiologically based pharmacokinetic (PBPK) model and used a stochastic simulator for the system of equations that we derived. We then coupled kinetics simulations with a deterministic hockey stick model of carcinogenicity. Stochasticity induced substantial modifications relative to dose-response curve, compared with the deterministic situation. In particular, there was nonlinearity in the response and the stochastic apparent threshold was lower than the deterministic one. The approach that we developed could easily be extended to other biological studies to assess the influence of stochasticity at macroscopic scale for compound dynamics at the cell level.

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