Combined Actions and Interactions of Chemicals in Mixtures

6 Interactions in toxicokinetics
Prepared by John Chr. Larsen
6.1 Toxicokinetics
Toxicokinetic interactions occur when the disposition of a toxic compound, i.e. its
absorption, distribution (including localisation at the target site), biotransformation
or excretion is altered by exposure, either simultaneously or displaced in time, to
another compound. The toxicological net-outcome of a toxicokinetic interaction
depends on whether a higher or lower level of the biologically active species is
achieved at the target site and/or whether the target site is exposed for a shorter or
longer duration.
6.1.1 Interactions with absorption
Absorption of chemicals from the gastro-intestinal tract is usually a passive
diffusion-driven process. Interactions are mainly to be expected when an active
transport process or a specific transporter is involved (Feron et al. 1995c). For
example, iron is known to decrease the gastro-intestinal absorption of cadmium
presumably by competing for the proteins involved in the transport of cadmium,
and thus protects against cadmium accumulation and toxicity in experimental
animals (Groten et al. 1991). This makes iron deficient women a particular risk
group for cadmium toxicity due to increased uptake from the gastrointestinal tract.
As regard absorption through the skin it is well known that surface-active
compounds and skin irritants can enhance the absorption of other chemicals (see
chapter 7.1.2.2)
6.1.2 Interference with distribution
Chemicals are distributed throughout the body via the bloodstream (or the lymph in
special cases). Lipophilic compounds are to a large extent bound to proteins in the
blood instead of just dissolved in water. A more lipophilic compound may remove
a less lipophilic substance from the binding site and thus severely increase the
concentration of unbound compound available for toxicological effect. This
situation is well known for medical drugs administered simultaneously (Feron et al.
1995c).
6.1.3 Interference with biotransformation
The majority of compounds that enter the organism require metabolism in order to
be excreted. If the parent compound is responsible for the toxicity and its
metabolites are less toxic an increased biotransformation rate will reduce the
toxicity, and conversely. However, if the chemical’s toxicity is mainly due to its
metabolite stimulating the biotransformation will enhance the toxicity.
There are numerous possibilities for interactions among chemicals at the level of
the enzymes involved in the biotransformation processes. Such interactions may in
principle be due to competition for a given enzyme or cofactor. Well known
examples are the detoxification of different alkylating agents by conjugation with
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