Combined Actions and Interactions of Chemicals in Mixtures

Physicochemical interactions will therefore not be considered in any detail in this
report.
The processes leading to a biological and/or toxicological response from exposure
of animals and humans to a given chemical can be divided into two distinct parts,
toxicokinetics and toxicodynamics (Renwick 1993, IPCS 1994). Toxicokinetics
relates to those processes that determine the extent and duration of exposure at the
target organ or site of toxicity to the active chemical species (parent compound or
metabolite). Toxicokinetics involves processes such as absorption, distribution,
biotransformation, and excretion of the compound and metabolites.
Toxicodynamics refers to the processes involved in the translation of such
exposure of the target organ or site of action into the generation of a toxic effect.
Toxicodynamics may involve a large number of different processes that determine
the mechanisms of action of a given chemical. These processes may involve
inhibition of cellular enzymes, damage through binding to proteins or DNA, or
interactions at endogenous receptor sites, just to mention a few events that may
pertubate the normal homeostasis of the organism or tissue.
2.2 No interaction
According to Plackett and Hewlet (Table 1.3.1) there are two types of combined
action without interaction: simple similar action (dose addition, Loewe additivity)
and simple dissimilar action. This latter type contains two concepts: effect or
response additivity and Bliss independence. The independence criterion seems not
to be widely used in toxicology (Groten et al., 2001). The response to a mixture of
compounds depends not only on the dose, but also on the correlation of tolerances
between the effects of the chemicals in the mixture, which can vary between –1
and +1 (Bliss 1937). There is a complete negative correlation (r =-1) between the
effects of two chemicals if the individuals that are most susceptible to one toxicant
are least susceptible to the other, while a complete positive correlation (r = +1)
exists if the individuals most susceptible to one toxicant are also most susceptible
to the other.
2.2.1 Simple similar action (dose addition, Loewe additivity)
Simple similar action (simple joint action or concentration/dose addition) is a noninteractive
process in which the chemicals in the mixture do not affect the toxicity
of one another. All the chemicals of concern in the mixture act on the same
biological site, by the same mechanism of action, and differ only in their potencies.
The correlation of tolerances is completely positive (r = +1) and each chemical
contributes to the toxicity of the mixture in proportion to its dose, expressed as the
percentage of the dose of that chemical alone that would be required to obtain the
given effect of the mixture. Thus the individual components of the mixture act as if
they were dilutions of the same toxic compound and their relative potencies are
assumed to be constant throughout all dose levels. An important implication is that
in principle no threshold exists for dose additivity.
Simple similar action serves as the basis for the use of “toxic equivalency factors”
often used to describe the combined toxicity of isomers or structural analogues.
Additive effects are described mathematically using summation of doses of the
individual compounds in a mixture adjusted for differences in potencies. This
method is assumed to be only valid for compounds that produce linear dose
response curves. Probably, the best validated example of a group of compounds
that obey the principles of simple similar actions are the dioxins (polychlorinated
dibenzo-p-dioxins and dibenzofurans) that produce most (if not all) of their
toxicities through interaction with the Ah-receptor.
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