Combined Actions and Interactions of Chemicals in Mixtures

no internationally accepted procedure for such a toxicological evaluation except for
the few groups of pesticides sharing a group ADI.
A well-known example is the group ADI of 0-0.03 mg/kg bw/day allocated to
dithiocarbamate fungicides. Thus, the Joint FAO/WHO Meeting on Pesticide
Residues (JMPR) in 1993 in its evaluation of Mancozeb concluded that “the data
on mancozeb would support an ADI of 0-0.05 mg/kg bw, based on the NOAEL of
4.8 mg/kg bw/day for the thyroid effects in rats using a 100 fold safety factor.
However, the Meeting established a group ADI of 0-0.03 mg/kg bw for mancozeb,
alone or in combination with maneb, metiram, and/or zineb, because of the
similarity of the chemical structure of these compounds, the comparable
toxicological profiles of the dithiocarbamates based on the toxic effect of
ethylenethiourea (ETU), the main common metabolite, and the fact that parent
dithiocarbamate residues cannot be differentiated using the presently-available
analytical procedures”.
The Danish Veterinary and Food Administration have up till now evaluated
mixtures of pesticides found as residues in crops by using the following two
practices:
- Summation of the concentrations of all residues and applying the ADI for
the most toxic pesticide found – this is the most restrictive assessment.
- Using the sum of the percentage of the ADI of the individual pesticides
found.
However, the report from the Bichel-commitee recommended that knowledge of
combined action should be taken more into account in the risk assessment of
pesticides (Bichel-udvalget, 1999). Therefore the Danish Veterinary and Food
Administration carried out a project in which the current knowledge about
combined toxic effects of mixtures of pesticides (the active substances of pesticide
formulations) published in the scientific literature was summarised and evaluated
(Reffstrup, 2002). The objective was to examine whether there is a scientific basis
for using a general standard formula in the risk assessment of pesticide mixtures.
This was done in order to ascertain and/or improve the toxicological risk
assessment of pesticide mixtures which humans are exposed to via food. The main
points and conclusions in the report were:
Two different kinds of approaches for health risk assessment of chemical mixtures
have been recommended in the literature, namely whole mixture approaches and
component-based methods. The assessment of whole mixtures can be done on the
mixture of concern, on a sufficiently similar mixture, or on a group of similar
mixtures. These assessments would be ideal for risk assessment of pesticide
residues in food, however they are not applicable in these cases since the methods
are very data intensive. This leaves the single compound approaches as the more
realistic ones.
For mixtures in which the compounds are toxicologically similar (e.g. same
mechanism of action), four methods based on simple similar action (Loewe
additivity) have been suggested: the hazard index, the relative potency factor
method, and the special type of the relative potency factor method named the
toxicity equivalency factor, and the margin of exposure approach. These methods
differ by the required data on toxicological processes but in all cases the exposure
levels are added after having been multiplied by a scaling factor that accounts for
differences in the toxicological potency. For compounds acting independently
(different mechanism of action) the response addition approach have been
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