Combined Actions and Interactions of Chemicals in Mixtures

describe toxicities that appears to be similar albeit the mechanism is not known in
details. For several groups of endocrine disrupters this terminology seems
appropriate.
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 (Wilkinson et al.
2000). 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.
For acute and short-term exposures difference in the toxicokinetic properties,
which will result in different times to maximum effect for the individual
compounds, are critical in determining concurrency at the target site. Therefore,
exposure intervals and the sequence of exposures to different chemicals may have
significant impact on the potential cumulative effect.
The risk assessment of exposure to mixtures of defined chemicals should make
optimal use of the toxicological databases. Ideally, in the opinion of Wilkinson et
al. (2000) 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 an artefact of 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 most chemicals will not permit an
estimation of for instance ED10 and relative potencies may have to be based on
NOAELs as PODs.
In describing the various procedures proposed to evaluate the risk associated with
combined exposure to a group of chemicals with a common mechanism of action
Wilkinson et al. (2000) emphasise that the biggest problem associated with all
methods of cumulative risk assessment is how to accommodate the different
uncertainty factors (UF) that are applied to derive regulatory values such as ADIs
or RfDs. If the uncertainty factors applied are the same for all the chemicals, all the
methods will give the same result. However, this is most often not the case and the
different uncertainty factors applied to the various chemicals will dominate the
result of the risk assessment. In order to illustrate this, exposure to a hypothetical
group of four common mechanism chemicals, differing in potency by 100-fold and
having exposures ranging from 0.01 to 0.5 mg/kg bw/day, was assessed assuming
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