Stochasticity in Physiologically Based Kinetics Models: Implications for Cancer Risk Assessment

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.