Toxicokinetics
Toxicokinetics can be defined as the way a chemical acts in the body, as referred above. This area of toxicology is divided into the following four components (fig. 1):
- Absorption
- Distribution
- Metabolism or biotransformation
- Excretion
These four factors in combination govern the degree of toxicity, if any, from chemical exposure. For example, a chemical may be absorbed but never reach a concentration at the target location above a threshold level. Or the chemical might be absorbed at concentrations high enough to cause toxicity, but the chemical is not distributed to the organ in which it can cause toxicity. As a consequence, no toxicity will result even though the amount absorbed was above a threshold level. Alternatively, a chemical might reach a target organ in sufficiently high levels to cause toxicity, but specific activities of cells in that organ change the structure of the chemical so that it is less toxic. Thus and again, a dose that is high enough to cause toxicity leads to no effects. Finally, a chemical could be eliminated from the body so fast that it never builds up in tissues at concentrations high enough to cause toxicity. These processes can happen simultaneously, and may either increase, decrease, or not affect the toxicity of a given chemical, depending on the magnitude and direction of each component. Furthermore, the physiological and biochemical attributes characteristics of a particular species can shift patterns of absorption, distribution, metabolism, excretion, or effect in significant ways. Each of these 4 toxicokinetic components is discussed below.
Absorption - is defined as the transfer of a chemical - across biological membranes - from the site of exposure, usually an external or internal body surface (e.g.: skin, mucosa of the alimentary and respiratory tracts), into the systemic circulation (i.e., the body). A chemical must be dissolved to be absorbed. The rate of absorption is related to the concentration of the chemical at the absorbing surface, which depends on the rate of exposure and the dissolution of the chemical. It is also related to the area of the exposed site, the characteristics of the epithelial layer through which absorption takes place and the physicochemical properties of the contaminant. Lipid solubility is usually the most important property influencing absorption. In general, lipid-soluble chemicals are absorbed more readily than are water-soluble substances. Therefore, lipid (i.e., fat) solubility and size of the molecule govern the rate and overall degree of absorption for a given chemical. Not all chemicals can be absorbed, and there can be large differences in the extent and rate at which absorption occurs.
Disposition - Unlike absorption, disposition consists not just of one kind of process but, rather, of a number of different kinds of processes taking place simultaneously. Disposition includes both distribution and elimination, which occur in parallel in almost all cases and are often considered independently of each other (Fig. 2). Elimination is also made up of two kinds of processes, excretion and biotransformation (or metabolism), which usually also take place simultaneously. Excretion is a physical mechanism, whereas biotransformation can involves several reactions to produce metabolites that can be easily eliminated from the organism. If a substance is effectively excreted, it will not be distributed into peripheral tissues to any great extent. On the other hand, wide distribution of the compound may impede its excretion.
A schematic overview of the different processes a pollutant can be subjected to as it enters the body of an aquatic organism can be observed in figure 3.
Distribution - Once a chemical is absorbed into the body, it is
distributed to certain organs via the circulatory system. How a
chemical is distributed in the body in part governs the target organ
for that chemical, how long it may take to act, how long and where it
will persist in the body, and how easily it is eliminated from the
body. Therefore, distribution defines where a chemical goes in the body
after absorption. For some chemicals, distribution and consequently,
the target organ differ depending on how or where it was absorbed (e.g.:
skin or gills). However, for other chemicals, distribution is the same
regardless of how and where absorption occurred. In addition to
defining where a chemical goes, distribution also addresses the
percentage of a chemical dose that goes to different locations. The
primary factors that govern where a chemical will be distributed in the
body include the blood flow to a particular tissue or organ, and the
relative affinity of that tissue or organ for the chemical.
Redistribution - is defined as the phenomenon of a chemical having two different destinations over time. For example, a chemical like dioxin may first be distributed to the liver, but the amount in the liver will decrease with time as some reenters the blood supply and reaches fat cells. Some will also be metabolized by and interact with the liver. However, the dioxin not affected by the liver will likely reach the fat cells, thus having two different destinations over time.
Elimination
The ability to efficiently eliminate toxic materials is critical to the survival of a species. The complexity of contaminant elimination processes has increased commensurate with the increased complexity associated with animal form (from unicellular to multiorgan organisms). For unicellular organisms, passive diffusion can be sufficient for the elimination of toxic metabolic produced by the organism. However, as organisms evolved in complexity - e.g. their bodies compartmentalized (i.e., cells, tissues, organs) and they developed barriers (e.g.: scales, skin) to the external environment -, several consequences of increased complexity compromise the efficiency of the passive diffusion of toxic chemicals (i.e., the elimination of toxic constituents of the organisms). This leads to the development of specialized routes of excretion. These routes generally evolved in concert (i.e., coevolved) with biotransformation processes that render chemicals amenable to these modes of excretion.
As an example, the main removal processes in aquatic organisms - referred to as elimination or depuration - are diffusive transfer across gill surfaces and intestinal walls, and biotransformation to metabolites that are more easily excreted than the parent compound.
Note: A generally accepted indicator of the rate of elimination of a contaminant is its "half-life" (t1/2), which is the time required to remove 50% of this contaminant from the bloodstream.
Metabolism or biotransformation - involves a process of biotransformation in which the chemical structure of the xenobiotic is changed. This change typically increases the water solubility of the chemical, which reduces the ability of the chemical to be stored in the fat, increases its rate of elimination by speciallized organs, and thereby greatly increases the rate of elimination for the chemical. Thus, this process can involve enzymes that convert the chemical into a form (called a metabolite) which is more readily excreted. However, the problem with metabolism is that it can sometimes convert the chemical into a more reactive toxic form. In this way, metabolism can either increase or decrease the toxicity. The liver is the primary site of chemical metabolism, so it is not surprising that blood flow is high to this organ. Biotransformation or metabolism reactions, and the factors that influence them, are discussed in detail in Chapter 7.
Excretion - is defined as the removal of the chemical from the body - through urine, faeces, sweat, breath, etc. - and their return to the external environment. The contaminants are excreted (rapidly or slowly) as the parent chemicals, as their metabolites, and/or as conjugates of them. The route and speed of excretion depend largely on the physicochemical properties of the compound. The kidney (via urine) is probably the single most important excretory organ in terms of the number of compounds excreted. But the liver and lungs are also important excretory organs for certain types of compounds. The lung (via exhalation) is active in the excretion of volatile compounds and gases. The liver, because it is a key biotransforming organ as well as an organ of excretion, is in a unique position with regard to the elimination of foreign chemicals. These chemicals can be eliminated into the bile or returned to the blood for renal elimination. In addition, there are a number of other minor routes for excretion (e.g.: sweat, skin).
