Combined Actions and Interactions of Chemicals in Mixtures

vivo. The COMET-assay in vivo and genotoxicity tests in transgenic animals might
be promising in vivo tests for future evaluation of complex mixtures.
Carcinogenesis is often described as a multi-step process. The fact that different
chemical, physical or biological agents may affect either step makes it obvious that
cancer is most often the result of combined actions. The interaction of carcinogens
affecting different steps in carcinogenesis has been known for half a decade to
cause synergistic effects, strongly increasing the tumour response. Thus, initiators,
promoters, converters, and co-carcinogens all act in concert to potentiate the final
tumour outcome. Anticarcinogens may prevent or inhibit cancer at either step, and
are also known to potentiate each other in some cases. Compounds affecting the
same step by different mechanisms can also cause potentiation. The possibilities
for combined effects in carcinogenesis are therefore many
In the area of reproductive effects, studies using combined exposure of two or more
chemicals have shown that interactions may or may not occur, and that it is
impossible to predict the outcome based on experimental conditions alone.
However, the published data suggest that the prevailing outcome of exposure to
mixtures deduced from in vivo experiments is either an antagonistic effect or no
interactive effect, including an additive effect. Frequently, one type of interaction
was noted at some doses, while another type of interaction was noted at other
doses. An evaluation of the results suggests that low doses of the chemicals in
combination often produced either no effect or additive effects, whereas higher
doses produced antagonistic or synergistic effects.
Most of the work made within the field of endocrine disruption is based on in vitro
experiments and only very few in vivo experiments on mixtures have been
performed so far. Such experiments will be one of the future challenges within the
field of endocrine disruption. The majority of the -especially older- studies
concluded that additive effects, i.e. no interaction between the compounds were
found, although detailed mechanistic analysis were not applied in most cases.
However, recent well-designed in vitro studies clearly show that the combined
effects of estrogenic compounds do not deviate from the expected additivity. In
addition, additive effects of two antiandrogenic compounds given in vivo were
found. Therefore, at present there is no evidence pointing to the necessity of
incorporating synergism in the hazard assessment of weakly estrogenic chemical
mixtures.
In neurotoxicity, there are many possibilities for interaction between chemicals
because of the complex hierarchical structure of the nervous system. A number of
examples have been described of which the most well known are the additive narcotic
effect of organic solvents, and the additive effect on acetyl cholinesterase inhibition by
organophosphorus insecticides. The strongest interaction found in the literature was a
5-fold increase in the neurotoxicity of hexane when methyl isobutyl ketone was coadministered.
However, very few quantitative studies have been performed and
interaction has not been studied systematically. Therefore, the present state of
knowledge does not allow general conclusions.
The many different cell types involved in the function of the immune system gives
many theoretical possibilities of combined immunotoxic effects. However, there are
as yet only few experimental data. Chemicals sharing a common toxic mechanism
seem to have an additive effect. Competition for metabolising enzymes may
antagonise the immunotoxic effect. How mixtures of chemicals that are toxic to
different branches of the immune system will exert their combined immunotoxic
effect remains to be established.
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