Combined Actions and Interactions of Chemicals in Mixtures

and now includes compounds as diverse as o,p’-DDT, methoxychlor, non-coplanar
PCBs, bisphenol A and alkoxyphenols.
Although there is evidence to suggest that some of these chemicals cause adverse
effects in wildlife, attempts to establish a link between human health risks and
exposure to estrogenic chemicals are complicated by the fact that many of the
suspected chemicals have very low estrogenic potencies when compared with 17ßestradiol.
Most of the chemicals are weak agonists or antagonists of the steroid
receptors being effective at concentrations in the µM range in vitro and thus are
several thousand folds less potent than the natural steroid hormones. It is therefore
difficult to explain possible health risks simply on the basis of toxicity from
exposure to the single compounds. However, human populations are exposed to
mixtures of xenoestrogens and it is conceivable that environmental contaminants
might interact with each other in a way that enhances their estrogenicity. Therefore,
studies on interaction effects of chemicals are a very important issue within the
field of endocrine disruption.
7.5.2 Examples of studies on interaction of endocrine disrupting
chemicals (EDCs)
Even though chemicals are usually found as mixtures in the environment, the
hormonal activity of mixtures has been investigated only to a limited extent and the
systematic analysis of combined effects of xenoestrogens has only recently begun.
The main focus so far of the effects of mixtures of EDCs has been on the
estrogenic activity of mixtures in cell cultures. It has to be kept in mind, though,
that the ability of certain chemicals to bind to and activate the estrogen receptor is
only one of the mechanisms, by which chemicals may interfere with the
development of the reproductive system. A number of other relevant in vitro
systems including assays for other hormone receptors or steroidogenic enzymes
still remain to be tested with mixtures of EDCs. In addition, the field of endocrine
disruption is naturally related to reproduction toxicology, but reports on interaction
of chemicals with the estrogen receptor is also belonging to the field of cancer
research, as for instance breast and prostate cancer.
The following is a summary of most of the studies on interaction between EDCs,
which have been reported, in recent years.
As early as 1994 Soto et al. demonstrated that a mixture of ten pesticides, at
concentrations that by themselves were inactive, enhanced the proliferation of
MCF7 human breast cancer cells by an effect which was classified as cumulative
by the authors. The involved pesticides were: endosulfan α and β, toxaphene,
dieldrin, tetrachlorbiphenyl, hexachlorbiphenyl, p,p’-DDT, -DDD, -DDE and
methoxychlor.
No dose-response curves were made and the study is an example of the application
of intuitively effect summation as described later. Thus, these data cannot be used
to analyse the mechanism of interaction, if any.
Later Sumpter and Jobling (1995) made preliminary experiments showing that
vitellogenin induction in cultured rainbow trout hepatocytes was ‘enhanced’ by a
combination of the following chemicals: 1 µM concentrations of nonylphenol,
octylphenol, o,p’-DDT, Arochlor 1221 and bisphenol A. Dose response curves of
the individual compounds were made, but no detailed analysis of the mechanism of
interaction was performed.
An example of mixtures of EDCs showing synergistic activity is a study employing
the use of turtle eggs (Bergeron et al. 1994). The sex of turtle eggs is temperature
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