Physiological modeling and extrapolation of pharmacokinetic interactions from binary to more complex chemical mixtures.

Abstract

The available data on binary interactions are yet to be considered within the context of mixture risk assessment because of our inability to predict the effect of a third or a fourth chemical in the mixture on the interacting binary pairs. Physiologically based pharmacokinetic (PBPK) models represent a potentially useful framework for predicting the consequences of interactions in mixtures of increasing complexity. This article highlights the conceptual basis and validity of PBPK models for extrapolating the occurrence and magnitude of interactions from binary to more complex chemical mixtures. The methodology involves the development of PBPK models for all mixture components and interconnecting them at the level of the tissue where the interaction is occurring. Once all component models are interconnected at the binary level, the PBPK framework simulates the kinetics of all mixture components, accounting for the interactions occurring at various levels in more complex mixtures. This aspect was validated by comparing the simulations of a binary interaction-based PBPK model with experimental data on the inhalation kinetics of m-xylene, toluene, ethyl benzene, dichloromethane, and benzene in mixtures of varying composition and complexity. The ability to predict the kinetics of chemicals in complex mixtures by accounting for binary interactions alone within a PBPK model is a significant step toward the development of interaction-based risk assessment for chemical mixtures.

A four-step approach to evaluate mixtures for consistency with dose addition

“…Physiologically based toxicokinetic (PBTK) models show potential in this regard. For example, PBTK models derived from kinetics studies on binary mixtures have been shown to predict toxicity for more complex mixtures (Krishnan et al, 2002). Further, research on integrating exposure assessments with PBTK models offers a promising approach for extending single route results to address multiroute scenarios (Arnold and Price, 2007).…”

Acute Treatment with Kerosene Damages the Dermal Barrier and Alters the Distribution of Topically Applied Benzo(a)pyrene in Mice

“…(23)(24)(25)(26)(27)(28) PAC are highly lipophilic and can be absorbed through intact skin to an appreciable extent. (29) However, once the skin is contaminated with PAC the exposed person may take actions to remove materials from the skin that may have a positive or negative impact on the PAC absorption.…”

The Toxicology of Chemical Mixtures Risk Assessment for Human and Ecological Receptors

“…When additivity can not predict the response, one or more interactions must be incorporated. Binary interactions for each possible pair of chemicals are added to the model; modeling of pairwise chemical interactions has been shown to be sufficient to describe the effect of the entire mixture (ATSDR, 2001a;Krishnan et aL, 2002;Tardif et aL, 1997). Interactions may be PK or PD in nature or a mixture may contain chemicals resulting in both types of relationships.…”

“…PBPK models account for binding to a substrate. When competitive chemicals are present, the inhibition constant can be determined experimentally from pairwise interactions (Tardiff et al, 1997) or it can be assumed equal to the interacting chemical's affinity constant (Andersen et aL, 1987;Dennison et aL, 2004;EI-Masd et aL, 1997;Krishnan et aL, 2002). Metabolism of one chemical may deplete the amount of enzyme or co-factor available for metabolism of a second chemical.…”