Chapter 7: Toxicokinetics

INTRODUCTION

Toxicokinetics refers to the quantitative study of absorption, distribution, metabolism, and excretion (ADME) of chemicals in biota through measurement and modeling of their concentrations or amounts in biological matrices (e.g., blood, plasma, excreta, exhaled air, tissues) as a function of time. Experimental studies of toxicokinetics facilitate the characterization of the temporal profile of the concentration of chemicals and their metabolites in the target tissue or other biological matrices, reflective of the net effect of the rate and extent of absorption through one or more exposure routes, distribution to tissues and organs via systemic circulation as well as disposition by metabolism and excretion (Fig. 7-1). The experimental and quantitative approaches used today for characterizing toxicokinetics of xenobiotics were derived from such studies extensively conducted with drugs over the past decades (traditionally known as pharmacokinetics) (Gibaldi and Perrier, 1975, 1982; O'Flaherty, 1981; WHO, 1986; Rescigno, 1997; Tozer and Rowland, 2006). Toxicokinetic data and analyses constitute an essential part of systematic approaches to safety/risk evaluation of xenobiotics and other substances including therapeutic drugs.

A fundamental goal of toxicokinetics is to facilitate the determination of dose delivered to the organism in view of understanding systemic exposure to the toxicant. For a scientifically sound interpretation of toxicology studies and characterization of dose–response relationships, it is preferable to relate adverse responses to the dose delivered to the target organ (or to systemic circulation) in the form of putative toxic moiety. In fact, the relationship between administered dose and adverse responses is better understood when the toxicokinetic data or models are used to translate the administered dose in terms of a relevant measure of internal dose (i.e., dose metrics) (U.S. EPA, 2006, 2014). Consistent with the current understanding of the mode of action of a particular chemical, the dose metrics reflect the intensity and level of a toxicologically active form of the chemical in the target or surrogate compartment during a specific period (Table 7-1). In this regard, the maximal blood concentration (C_max), the area under the blood concentration versus time curve (AUC) and the amount metabolized are the common dose metrics used in interpreting toxicity data. Fig. 7-2A presents a time course of the blood concentration of a chemical following its administration via the oral route. The C_max and AUC can be obtained following such time-course measurements of chemical concentrations in plasma, blood, or tissues in toxicokinetic studies. However, due to ethical and feasibility considerations, toxicokinetic data cannot always be obtained for ...