Something from “Nothing” − Eight Weak Estrogenic Chemicals Combined at Concentrations below NOECs Produce Significant Mixture Effects

Abstract

We tested whether multicomponent mixtures of xenoestrogens would produce significant effects when each component was combined at concentrations below its individual NOEC or EC01 level. The estrogenic effects of eight chemicals of environmental relevance, including hydroxylated PCBs, benzophenones, parabenes, bisphenol A, and genistein, were recorded using a recombinant yeast estrogen screen (YES). To ensure that no chemical contributed disproportionately to the overall combination effect, a mixture was prepared at a mixture ratio proportional to the potency of each individual component. The performance of four approaches for the calculation of additive combination effects (concentration addition, toxicity equivalency factors, effect summation, and independent action) was compared. Experimental testing of the predictions revealed that concentration addition and its application, the toxicity equivalency factor approach, were valid methods for the calculation of additive mixture effects. There was excellent agreement between prediction and observation. In contrast, independent action and effect summation led to clear underestimations of the experimentally observed responses. Crucially, there were substantial mixture effects even though each chemical was present at levels well below its NOEC and EC01. We conclude that estrogenic agents are able to act together to produce significant effects when combined at concentrations below their NOECs. Our results highlight the limitations of the traditional focus on the effects of single agents. Hazard assessments that ignore the possibility of joint action of estrogenic chemicals will almost certainly lead to significant underestimations of risk.

Endocrine disruptors in bottled mineral water: total estrogenic burden and migration from plastic bottles

“…Since the assays used in this study integrate all xenoestrogens present in the samples, we propose that there are either potent estrogenic mixtures causing the in vitro and in vivo effects Silva et al 2002) or so far unidentified compounds with strong estrogenic potency.…”

Combined effects of estrogenic chemicals with the same mode of action using an estrogen receptor binding bioassay

“…Although the paper was retracted the following year because the result was lack of reproducibility in other laboratories (McLachlan, 1997), it led to academic concern and intense follow-up research. There have been lots of researches to study the effects of estrogenic mixtures on organisms ranging from recombinant yeasts and estrogen-sensitive cells (Arnold et al, 1997;Payne et al, 2001;Rajapakse et al, 2004;Silva et al, 2011Silva et al, , 2002Suzuki et al, 2001) to vertebrates such as fish and mice (Brian et al, 2007;Ramamoorthy et al, 1997;Ribeiro et al, 2012;Sun et al, 2009;Thorpe et al, 2005;Tinwell and Ashby, 2004). Among these test organisms, the recombinant human ER gene yeast obtained wide application because it provided not only fast and sensitive detection but also single MoA and ToA.…”

Seabirds as regional biomonitors of legacy toxicants on an urbanized coastline

“…At high concentrations, toxicants can reduce individual survival and reproduction, resulting in population decline (Bustnes et al, 2003;Hellou et al, 2013). Even at sub-lethal levels, these toxicants can impair physiological, immune, and reproductive function (Finkelstein et al, 2007;Tartu et al, 2013;Goutte et al, 2015) and in some species, combinations of toxicants even below effects thresholds have been linked to endocrine disruption (Silva et al, 2002;Bryan et al, 2005). Though effects vary by species, contaminant type, and concentration, the impacts have been observed in multiple taxa and are severe enough to warrant regular screening.…”