Academic journal article Environmental Health Perspectives

Combining Xenoestrogens at Levels below Individual No-Observed-Effect Concentrations Dramatically Enhances Steroid Hormone Action. (Articles)

Academic journal article Environmental Health Perspectives

Combining Xenoestrogens at Levels below Individual No-Observed-Effect Concentrations Dramatically Enhances Steroid Hormone Action. (Articles)

Article excerpt

The low potency of many man-made estrogenic chemicals, so-called xenoestrogens, has been used to suggest that risks arising from exposure to individual chemicals are negligible. Another argument used to dismiss concerns of health effects is that endogenous steroidal estrogens are too potent for xenoestrogens to contribute significantly to estrogenic effects. Using a yeast reporter gene assay with the human estrogen receptor [alpha], we tested these ideas experimentally by assessing the ability of a combination of 11 xenoestrogens to affect the actions of 17[beta]-estradiol. Significantly, each xenoestrogen was present at a level well below its no-observed-effect concentration (NOEC). To derive accurate descriptions of low effects, we recorded concentration-response relationships for each xenoestrogen and for 17[beta]-estradiol. We used these data to predict entire concentration-response curves of mixtures of xenoestrogens with 17[beta]-estradiol, assuming additive combination effects. Over a large range of concentrations, the experimentally observed responses decisively confirmed the model predictions. The combined additive effect of the 11 xenoestrogens led to a dramatic enhancement of the hormone's action, even when each single agent was present below its NOEC. Our results show that not even sub-NOEC levels of xenoestrogens can be considered to be without effect on potent steroidal estrogens when they act in concert with a large number of similarly acting chemicals. It remains to be seen to what degree these effects can be neutralized by environmental chemicals with antiestrogenic activity. Nevertheless, potential human and wildlife responses induced by additive combination effects of xenoestrogens deserve serious consideration. Key words: 17[beta]-estradiol, additivity, mixture effects, xenoestrogens, yeast estrogen screen (YES). Environ Health Perspect 110:917-921 (2002). [Online 12 August 2002] http://ehpnet1.niehs.nih.gov/docs/2002/110p917-921rajapakse/abstract.html

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The enormous discrepancies between the high concentrations of xenoestrogens often required to produce effects in laboratory assays and their low levels in human tissues and the environment have fueled the belief that synergisms between these chemicals need to be invoked to explain possible health risks to humans and wildlife. However, initial reports of strong synergisms between binary combinations of estrogenic pesticides (Arnold et al. 1996) could not be reproduced (Ashby et al. 1997; Ramamoorthy et al. 1997) and had to be withdrawn (McLachlan 1997). Furthermore, numerous tissues contain potent steroidal estrogens at biologically active levels. This has led to the view that exposure to xenoestrogens may not pose any harm because they are unable to impact the strong effects of steroidal estrogens (Safe 1995).

However, the perceived "weakness" (or otherwise) of a xenoestrogen alone does not necessarily signal absence of risks, when considering the effects of xenoestrogens in relation to potent steroidal estrogens. In a recent study of mixtures of estradiol and the weak xenoestrogens bisphenol A and o,p'-DDT (Rajapakse et al. 2001), we found that both the hormone and the xenoestrogens contributed in equal measure to the observed combination effects when combined at concentrations that produced similar responses. Furthermore, model calculations carried out by our group suggested that combinations of a large number of xenoestrogens might modulate the effects of 17[beta]-estradiol, even when each individual xenoestrogen is present at concentrations that alone would not produce measurable effects (Kortenkamp and Altenburger 1999). In view of the implications for hazard assessment, we set out to test this idea experimentally.

Mixture experiments involving a large number of chemicals place very high demands on the reproducibility of biologic responses. To meet these requirements, we used the yeast estrogen screen (YES) (Routledge and Sumpter 1996), which has proven to yield highly reproducible results (Payne et al. …

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