Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action.

Abstract

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 receptoralpha, we tested these ideas experimentally by assessing the ability of a combination of 11 xenoestrogens to affect the actions of 17ss-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 17ss-estradiol. We used these data to predict entire concentration-response curves of mixtures of xenoestrogens with 17ss-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.

Synergistic effects of perfluoroalkyl acids mixtures with J-shaped concentration–responses on viability of a human liver cell line

“…Certain evidence has indicated that adverse effects of mixtures could be induced from exposure to many compounds at or below NOEC Rajapakse et al, 2002;Ge et al, 2011). We assessed the joint effects of the eleven and nine individual PFAAs at IC 0 concentration corresponding to a true zero effective concentration in our test system.…”

Exposure assessment for endocrine disruptors: some considerations in the design of studies.

“…A cumulative risk approach goes beyond identifying effects of individual endocrine disruptors by considering the possibly additive, antagonistic, or synergistic activity of simultaneous exposures to many agents that may affect children's health (Rajapakse et al 2002). Future cumulative risk assessments will consider a) how exposures to multiple agents alter the toxicity of endocrine disruptors, b) how genes, life stages, lifestyles, and diseases can affect the toxicity of endocrine disruptors, and c) how exposure to endocrine disruptors can alter the toxicity of other agents.…”

Monofluorinated Analogues of Polybrominated Diphenyl Ethers as Analytical Standards: Synthesis, NMR, and GC-MS Characterization and Molecular Orbital Studies

“…Partial agonists only partially fulfill this requirement and thus cause the mixture curves to deviate from that of E2 at higher concentrations. The difficulty of predicting maximum effect levels of mixtures containing partial agonists with the CA model is also discussed by others (3,11). In our experiments, MILs of mixtures containing partial agonists could, however, roughly be estimated by calculation of the average MIL of the mixture components, weighted by their relative contributions to the total estrogenic activity of the mixture (last column in Table 2).…”

“…The contribution of each component to the total effect of the mixture is considered to be proportional to its estrogenic potency and its concentration in the mixture. The CA concept has previously been shown to be valid for the prediction of mixture effects of estrogenic compounds in the yeast estrogen screen (YES assay) (3,11,12). Like the YES assay, the ER-CALUX assay is based on a receptor gene construct, with activation of the endogenous estrogen receptors as the sole molecular mechanism leading to response.…”