Combined Actions and Interactions of Chemicals in Mixtures

suggested, and for compounds that interact, use of interaction hazard index have
been suggested.
Several reports have suggested that since the pesticides are found in food at levels
well below their respective no observed adverse effect levels (NOAEL), the
approaches based on toxicologically similar mechanism (same mechanism of
action) and toxicological independence (different mechanism of action) should be
used for risk assessment of pesticide residues. In fact, it has been suggested that
methods for toxicologically similar compounds could be used in most cases, even
when the compounds are not toxicologically similar.
The present knowledge about combined toxic effects of mixtures of pesticides (the
active substances of pesticide formulations) that have been published in the
scientific literature were summarised and evaluated in the report in order to test the
hypothesis behind the risk assessment models presented. The in vivo studies on
pesticide mixtures were performed at high doses (ten times NOAEL or higher)
compared to the expected pesticide residues in food. Studies employing high doses
have shown both additivity and interactions such as synergism or coalism as well
as antagonism. None of the studies reported in the literature used low pesticide
doses, in the range normally found for residues in food. Furthermore, the number
of theoretical possible pesticide mixtures is enormous compared to the number of
mixtures studied and published in the scientific literature and the overall quality of
the data in the studies is not good enough to reach a clear conclusion. Therefore it
was concluded that there is no scientific background for establishing a general
standard formula for risk assessment of pesticide mixtures in food. However,
studies on other chemical mixtures at low doses have been found not to
demonstrate a risk different from that of the single compounds in the mixture. The
authors of these studies have concluded that combined exposure to arbitrarily
chosen chemicals did not demonstrate more than an additive action when all
chemicals in the mixture were administrated at their own individual NOAELs (see
chapter 5).
In the report it is suggested to use the flow chart shown in figure 4.6.3.1 for risk
assessment of pesticide mixtures in crops. The risk assessment of pesticide
mixtures in crops should be done by a case-by-case evaluation in which the
available chemical and toxicological data on the pesticides are evaluated in a
weight of evidence process. Then the hazard index with the ADI (where the
individual safety factors are included) and not the NOAEL’s (where the safety
factors are not included) as the acceptable level in the denominator is
recommended for use. However, in cases where the weight of evidence process
points out that the compounds in the mixture share a common mechanism (e.g. for
the organophosphorus pesticides), the toxicity equivalency factor (TEF) approach
should be used, if possible (Reffstrup 2002).
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