Combined Actions and Interactions of Chemicals in Mixtures

and antagonistic effects may be seen, dependent on the compounds. When the
exposure levels are at the ADI/TDI levels no greater hazard is to be expected.
The Dutch group is of the opinion that the use of the “dose addition” approach to
the risk assessment of chemical mixtures is only scientifically justifiable when all
the chemicals in the mixture act in the same way, by the same mechanism, and thus
differ only in their potencies. Application of the “dose addition” model to mixtures
of chemicals that act by mechanisms for which the additivity assumptions are
invalid would greatly overestimate the risk.
An ILSI (International Life Science Institute) Working Group has recently
addressed the “common mechanism” issue. The ILSI Working Group concluded
that a common mechanism might exist if two compounds:
• Cause the same critical effect
• Act on the same molecular target at the same target tissue, and
• Act by the same pharmacological mechanism of action and may share a
common toxic intermediate
It should be realised that with the exception of a few groups of chemicals, such as
some organophosphorous and carbamate pesticides and some polychlorinated
dibenzo-p-dioxins, - dibenzofurans and - biphenyls, precise mechanistic
information on their toxic effects are scarce.
Another critical issue is the question of concurrent exposure. This refers to coexposure
to more than one chemical able to interact with a defined target in a
specific target tissue during a particular time frame of interest. It is important to
distinguish between concurrent or simultaneously “external” exposure, referring to
the timing of oral, dermal or inhalation exposure, from concurrent “internal”
exposure that relates to the dose actually attained at a given biological target in a
given time frame. For the risk assessment it is the “internal” exposure that is of
toxicological significance, however, it is seldom known. The factors that determine
whether a cumulative effect is likely from exposure to several different common
mechanism compounds are the timing and duration of external exposure, the
persistence (biological half-life) of the chemicals in the body, and the duration of
the effect.
The effect of any chemical at a biological target depends of its ability to attain a
target site concentration that exceeds the threshold required to elicit the response.
The intensity and duration of the response depends on the toxicokinetic properties
of the compound (absorption, distribution, metabolism and excretion) and the
nature of the target site interaction (reversible, irreversible). If recovery is complete
between successive exposures no cumulative toxicity is to be expected. However, a
short-term acute exposure could potentially add to the long-term burden of a
persistent chemical and be relevant for the magnitude of the chronic effect.
The risk assessment of exposure to mixtures of defined chemicals should make
optimal use of the toxicological databases. Ideally, the point of departure (POD) for
the assessment should be a dose associated with a particular biological response
(ED10, ED20) since this takes into account all of the dose-response data available.
A POD based on doses causing a particular response should always take preference
over the NOAEL. This is because the NOAEL is a single point value and not a
measure of a biological response and is largely a consequence of the experimental
design. The POD should also ideally be based on studies with the same animal
species using the same route of administration. However, the data available for
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