Combined Actions and Interactions of Chemicals in Mixtures

Figure 4.4.1.1. Scheme for safety evaluation of simple mixtures
Dose additivity (similar
mode of action?)
4.4.2 Complex mixtures
Simple mixtures
Test individual
components and
combination of
components
Response or effect
additivity (dissimilar
mode of action or
independent action?)
Hazard index, relative
potency, PBPK model
Data should be useful
for risk assessment
Deviation from
additivity
(interaction)
Test entire mixture
Data should be
useful for risk
assessment
As regards complex mixtures the Feron group initially recommended a two-step
approach: First to identify the “n” (e.g. 10) most risky chemicals in the mixture,
and then to perform hazard identification and risk assessment of the defined
mixture of the (10) priority chemicals using procedures appropriate for simple,
defined mixtures (Feron et al. 1995a, 1995b, Cassee et al. 1998, Feron et al. 1998):
Figure 4.4.2.1. Two-step procedure for the safety evaluation of complex mixtures (Feron et
al. 1995b)
Step 1: Identification of priority chemicals
Select a limited number of chemicals (e.g. ten) with the highest risk potential, using
the risk quotient (RQ)
RQ =
Level of exposure
Level of toxicity
In other words, identify the “top ten” chemicals
Step 2: Hazard characterisation and risk assessment
Identify the hazard and assess the health risk of the defined mixture of the (“ten”)
priority chemicals, using approaches appropriate for simple mixtures of chemicals
A pragmatic approach: carry out limited toxicity studies e.g. one four-week rat study
and one screening assay for genotoxicity with the defined mixture of (“ten”) priority
chemicals, using exposure concentrations e.g. 3 – 10 times higher than those
occurring in the complex mixture
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