Payne, Joachim Peter; (2001) Xenoestrogens: assessing the predictability of mixture effects. Doctoral thesis (Ph.D.), University College London.

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Abstract

Recently there has been growing concern over the increasing incidence of endocrine related disorders in both humans and wildlife. This has prompted researchers to speculate about a common underlying environmental cause. A large number of natural and synthetic chemicals have been shown to interact with the estrogen receptor, and it is believed that these xenoestrogens are the agents responsible. We are constantly exposed to many such agents, however, the study of interactions between these chemicals within biological systems has often been hampered by the application of unsuitable models of mixture action. In this study we have employed, for the first time, the well-validated models of concentration addition and independent action to analyse xenoestrogen mixture effects in the MCF-7 cell proliferation assay and the yeast estrogen screen. Both models yield excellent predictions of mixture action in our test systems, and indicate that the xenoestrogens o,p'-DDT, p,p'-DDT, p,p'-DDE and (3-HCH act additively in the MCF-7 assay. Similarly, we observe that interactions between o,p'-DDT, 4-octylphenol, 4-nonylphenol and genistein are additive in the yeast estrogen screen. Assuming that additivity holds true in vivo, we have attempted to estimate the human exposure to xenoestrogens which would be required to significantly modulate the activity of estradiol. Our calculations indicate that at current levels of exposure these chemicals could pose a risk to human health. Although this estimate is by no means conclusive, we feel that a large step forward has been made in understanding xenoestrogen mixture effects.

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