# 4.1. Toxicokinetics

Author: Nico van Straalen

Reviewer: Kees van Gestel

Learning objectives:

You should be able to

- Describe the difference between toxicokinetics and toxicodynamics
- Explain the use of different descriptors for the uptake of chemicals by organisms under steady state and dynamic conditions

Keywords: toxicodynamics, toxicokinetics, bioaccumulation, toxicokinetic rate constants, critical body residue, detoxification

Toxicology usually distinguishes between toxicokinetics and toxicodynamics. Toxicokinetics involves all processes related to uptake, internal transport and the accumulation inside an organism, while toxicodynamics deals with the interaction of a compound with a receptor, induction of defence mechanisms, damage repair and toxic effects. Of course the two sets of processes may interact, for instance defence may feed-back to uptake and damage may change the internal transport. However, often toxicokinetics analysis just focuses on tracking of the chemical itself and ignores possible toxic effects. This holds up to a critical threshold, the critical body concentration, above which effects become obvious and the normal toxicokinetics analysis is no longer valid. The assumption that toxicokinetic rate parameters are independent of the internal concentration is due the limited amount of information that can be obtained from animals in the environment. However, in so called physiology-based pharmacokinetic and pharmacodynamic models (PBPK models) kinetics and dynamics are analyzed as an integrated whole. The use of such models is however mostly limited to mammals and humans.

It must be emphasized that toxicokinetics considers fluxes and rates, i.e. mg of a substance moving per time unit from one compartment to another. Fluxes may lead to a dynamic equilibrium, i.e. an equilibrium that is due to inflow being equal to outflow; when only the equilibrium conditions are considered, this is called partitioning.

In this Chapter 4.1 we will explore the various approaches in toxicokinetics, including the fluxes of toxicants through individual organisms and through trophic levels as well as the biological processes that determine such fluxes. We start by comparing the concentrations of toxicants between organisms and their environment (section 4.1.1), and between organisms of different trophic levels (section 4.1.6). This leads to the famous concept of bioaccumulation, one of the properties of a substance often leading to environmental problems. While in the past dilution was sometimes seen as a solution to pollution, this is not correct for bioaccumulating substances, since they may turn up elsewhere in the next level food-chain and reach an even higher concentration. The bioaccumulation factor is one of the best-investigated properties characterizing the environmental behaviour of a substance . It may be predicted from properties of the substance such as the octanol-water partitioning coefficient.

In section 4.1.2 we discuss the classical theory of uptake-elimination kinetics using the one-compartment linear model. This theory is a crucial part of toxicological analysis. One of the first things you want to know about a substance is how quickly it enters an organism and how quickly it is removed. Since toxicity is basically a time-dependent process, the turnover rate of the internal concentration and the build-up of a residue depend upon the exposure time. An understanding of toxicokinetics is therefore critical to any interpretation of a toxicity experiment. Rate parameters may partly be predicted from substance properties, but properties of the organism play a much greater role here. One of these is simply the body mass; prediction of elimination rate constants from body mass is done by allometric scaling relationships, explored in section 4.1.5.

In two sections, 4.1.3 and 4.1.4, we present the biological processes that underlie the turnover of toxicants in an organism. These are very different for metals than for organic substances, hence, two separate sections are devoted to this topic, one on tissue accumulation of metals and one on defence mechanisms for organic xenobiotics.

Finally, if we understand all toxicokinetic processes we will also be able to understand whether the concentration inside a target organ will stay below or just passes the threshold that can be tolerated. The critical body concentration, explored in section 4.1.7 is an important concept linking toxicokinetics to toxicity.