Our Stolen Futurea book by Theo Colborn, Dianne Dumanoski, and John Peterson Myers


for a more general discussion of mixtures...

  Payne, J, N Rajapakse, M Wilkins, and A Kortenkamp 2000. Prediction and Assessment of the Effects of Mixtures of Four Xenoestrogens. Environmental Health Perspectives 108:983-987.



Payne et al. examined the ability of several estrogen mimics to act alone and then in combination with one another, in an experimental system that examined the strength of an estrogen response measured in yeast cells in culture that had been genetically modified to contain human estrogen receptors. This assay is now well-established as a means to measure estrogenicity of compounds.

After carefully characterizing the dose-response curves of compounds by themselves, they performed experiments with combinations of the compounds. They then tested to see whether the impacts of combinations of compounds could be predicted on the basis of adding the observed impacts of the compounds when studied separately.

They found that the additions accurately predicted the impacts of the compounds together in mixtures.

This is important because it addresses a more general and vital question about the potential hazards of endocrine disrupters. Without exception, in the real world contaminants come in mixtures. Virtually all of regulatory toxicology, however, has focused on the actions of contaminants one-by-one. Do these one-by-one experiments help in anticipating how contaminants behave in mixtures? Do compounds cancel one another or multiply each others' impacts. [More...]

What did they do?
Payne et al. used four well-established estrogen mimics, o,pī-DDT, genistein, 4-nonylphenol, and 4-n-octylphenol, in the yeast estrogen screen (YES) system. These four compounds are all known to bind with the estrogen receptor. Payne et al. established dose response curves for each compound, describing the strength of the estrogen response for different concentrations of the compounds singly. They then combined the estrogen mimics in different mixtures and measured their total impact.

The crucial test was then to determine whether the total impact was predictable on the basis of the sum of the independent effects. So, for example, if a particular test mixture of DDT, genistein, nonylphenol and octylphenol contained concentrations of those compounds that separately had provoked estrogen responses (on some arbitrary scale) of 0.1, 3, 2.2 and 5, respectively, the question was whether the mixture provoked a response of 10.3 (the sum of the separate responses).

This need not have been the case. Compounds could have interfered with one another, decreasing the total response, even negating it. Or they might have interacted synergistically, causing a response in mixture significantly greater than a simple additive effect.


What did they find?
They found that the compounds interacted additively. The results of mixtures could be predicted by adding up their individual impacts.

As noted above, this is an important demonstration. It has several limitations, however, which limit its applicability to the real world. These limitations, discussed below, suggest that these results imply that interactions of these four compounds in live animals at a minimum would be additive. They might be much more.

First, this pioneering work tells us that some compounds interact additively, but work of this nature is too rare, as yet, to know whether this is a general pattern to expect with other compounds.

Second, the experimental system was purposefully made as simple as possible: compounds known to bind with the estrogen receptor with the assay being a direct measure of the result of receptor binding in an in vitro cell culture. They designed the experiment that way to limit the mechnisms of action to the one they could measure directly. Many compounds have more than one mechanism of action. Other mechanisms of action by the same compound might provoke other responses simultaneously that could alter the pattern of interaction.

Third, to simplify these experiments (and make interpretation as feasible as possible, they were done with a single type of cell in a monoculture. Mixtures in real animals interact with many different cells, organs and tissues simultaneously, with the potential for myriad positive and negative feedback loops.







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