Combined Actions and Interactions of Chemicals in Mixtures

obvious ranking of individual constituents according to their potential
health risks and the “top-ten” chemicals of the mixture are not easily
identified. This approach involves identification of the “top-ten”
classes of chemicals to be lumped together by class to the “top-ten”
chemicals to be treated as a simple mixture. The lumping technique is
based on grouping chemicals with relevant similarity such as the same
target organ or similar mode of action. The selected “top-ten”
chemicals are either chemicals representative of each class or pseudo
components representing a fictional average of a certain class. This
technique has been described by Verhaar et al. (1997) who proposed it
to be combined with QSAR and PBPK/PD (physiologically based
pharmacokinetic/pharmacodynamic) modelling in predicting the
toxicity of complex mixtures of petroleum products.
Groten et al. (2000) used the principle that joint actions and/or interactions could
possibly occur if chemicals shared a common target organ and produced similar
adverse effects to analyse all approved food additives allocated a numerical ADI (a
total of 65 additives). Target organs were identified based on the adverse effects
reported above the NOAELs in animal or human studies. Description of
pathological and other changes found were used to assess whether different
additives, sharing the same target organ, would produce a common toxic effect. In
many cases the adverse effects were considered to be non-specific and/or related to
nutritional/palatability problems, such that a clear target toxicity could not be
identified. Twelve different target organs were identified, and each group of
additives, sharing the same target organ, was studied in detail for possible joint
actions and/or interactions. In all but four cases, the possibility of joint actions
and/or interactions could be excluded on scientific grounds. The exceptions were
groups of additives with critical effects on the liver (curcumin, thiabendazole,
propyl gallate and butyl hydroxyl toluene), the kidneys (diphenyl, o-phenylphenol
and ferrocyanide salts), the blood (azorubine and propyl gallate), and the thyroid
(erythrosine, thiabendazole and nitrate). However, an in-depth analysis of both the
specific use and the intake levels of these four groups of additives led the authors
to conclude that joint actions or interactions among the additives in a group was a
theoretical rather than a practical concern (Groten et al. 2000).
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