Combined Actions and Interactions of Chemicals in Mixtures

Selection of the “top ten” chemicals in the first step should be based on the level of
exposure and level of toxicity of the individual chemicals. The higher the value of
the risk quotient (RQ) the higher the probability of adverse health effect in human
(e.g. higher risk) and the higher the chemical should rank on the list of priority
chemicals. The hazard identification and risk assessment of the mixture of selected
chemicals (the “top-ten” chemicals) should be based on toxicity data and on the
mechanism of action of the individual compounds and on the prediction of
presence or absence of additive or potentiating interactive effects. In order to
predict combined action (additivity) or interactions between the selected chemicals
knowledge about the presumed mechanism of action is necessary. Therefore, a
classification system of chemicals on the basis of their mechanism of action would
be extremely helpful. A classification could be based on:
• Similar or identical biotransformation pathways, including ability to induce or
inhibit biotransformation enzymes
• Similar or identical receptors for the compounds or their active metabolites
• Structural similarities pointing to either of the above.
The group recognises that a major practical problem is lack of information of
biotransformation and relevant receptor or target site of many chemicals. In such
cases, the chemicals should be classified using computer-based structure-toxicity
relationships and expert judgement and experience.
The evaluation assumes that the hazard and possible risk of the defined (“top-ten”)
mixture of chemicals are representative for the hazard and risk of the entire
complex mixture. For some mixtures, that are relatively easily available (e.g.
combustion fumes, food products, pesticide mixtures), this assumption could be
validated by comparing the toxicity of the “top ten” mixture with the toxicity of the
original complex mixture in short-term test.
The group has elaborated on their approach and provided a scheme (decision tree)
for hazard identification and risk assessment of complex mixtures (Feron et al
1998, Groten et al., 2001) (Figure 4.4.2.2). In this scheme it is suggested that:
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• For complex mixtures that are virtually unavailable for testing as a whole
(such as workplace atmospheres, coke oven emissions, atmospheres at
waste sites) the “top-ten” approach as mentioned above is suggested.
• For complex mixtures that are readily available for testing as a whole (such
as drinking water, diesel exhaust, welding fumes, tobacco smoke, pesticide
mixtures, food products) three possible approaches are suggested:
• Testing as a whole. This may characterise the toxicity profile of the
mixture and eventually verify the (presumed) safety or hazard from
exposure to mixture. One problem may be that incorporation of the test
material in the diet at a sufficiently high dose may result in an
unbalanced diet and nutritional deficiencies. Another problem is that
most mixtures may change in chemical composition over time.
• Identification of the “top-ten” chemicals to be treated as a simple
mixture. This should be considered as the primary option if the
available data on the composition and the toxicity profile of the
mixture indicate that the hazard is driven by a small number of the
constituents.
• The “pseudo top-ten” approach should be considered for mixtures
which consist of a large number of widely varying chemicals with no