Is it time to end concerns over the estrogenic effects of bisphenol A?

Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Toxicological Sciences (Impact Factor: 4.48). 03/2010; 114(1):1-4. DOI: 10.1093/toxsci/kfp299
Source: PubMed
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    • "Regarding EDs, aspects of hazard evaluation and applicability of the established risk assessment process have been questioned and are the subject of a strong debate within the scientific community (Ashby, 2003; Welshons et al., 2003; Phillips et al., 2008; Rhomberg and Goodman, 2012; Sharpe, 2010b; Vandenberg et al., 2009, 2012; vom Saal et al., 2010; Zoeller et al., 2012). The major points are related to the hypothesis that ED could (or not) (i) act with a non-threshold mechanism, (ii) give rise to a non-monotonic dose–response (NMDR) relationship, and (iii) at very low doses, particularly during critical windows of exposure. "
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    ABSTRACT: Some recent EU Regulations have focused on the potential risks posed by the presence of Endocrine Disrupters (ED) into the environment. However there are conflicting opinions on how to assess the risk from exposure to these molecules that can reversibly modulate hormonal activity, Endocrine Active Substances (EAS) rather than causing irreversible damage (ED).The present paper attempts to discuss that perturbation of normal endocrine homeostasis in itself may not be an adverse effect, since the endocrine system is naturally dynamic and responsive to various stimuli as part of its normal function and it is modulated according to the characteristic trend of the dose response curve.EDs should be evaluated using a weight-of-evidence (WoE) approach. If a chemical meets the criteria to be defined as an ED in experimental animals, the relevance of observed effects to the human then needs to be addressed.Hazard-based risk management is therefore not justified since does not meet the criteria for a sound scientifically-based assessment.
    Toxicology 08/2013; 314(1). DOI:10.1016/j.tox.2013.07.018 · 3.75 Impact Factor
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    • "Our comments below are a direct response to this particular review, but it should be noted that they also pertain more broadly to several earlier publications that have argued for the theory of low-dose nonmonotonicity of endocrine-mediated effects (e.g., vom Saal et al., 2007). These earlier arguments have drawn their own responses (e.g., Sharpe, 2010; Goodman et al., 2009). "
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    ABSTRACT: Vandenberg et al. (2012) claim that "most if not all [endocrine-disrupting chemicals (EDCs)] are likely to have low-dose effects" and "nonmonotonicity is a common occurrence after exposures to hormones and EDCs in cell culture and animals and across human populations." They present examples as anecdotes without attempting to review all available pertinent data, selectively citing studies without evaluating most of them or examining whether their putative examples are consistent and coherent with other relevant information. They assume that any statistically significant association indicates causation of an adverse effect, and their limited evaluation of specific studies is not done uniformly (i.e., studies with positive results are evaluated differently than those with null results). They also do not evaluate whether exposures in studies are truly "low-dose" and relevant to humans. They propose a number of different nonmonotonic dose-response curves, but do not consider reasons for why they should be expected to apply generally across species. Many of their examples would be - and indeed have been - questioned by many scientists. Overall, Vandenberg et al. put forth many asserted illustrations of their two conclusions without providing sufficient evidence to make the case for either and while overlooking evidence that suggests the contrary.
    Regulatory Toxicology and Pharmacology 06/2012; 64(1):130-3. DOI:10.1016/j.yrtph.2012.06.015 · 2.14 Impact Factor
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    • "BPA, regarded as a xeno estrogen, is a weak agonist of the estrogen receptor (ER) (Bondesson et al. 2009). Nevertheless, doubts remain whether BPA exerts adverse estrogenic effects in animals and humans (Sharpe 2010; Vandenberg et al. 2009). Many EDCs, including organochlorine and organophosphate pesticides, alkyl phenols, phthalates, and polychlorinated biphenyls (PCBs) activate another nuclear receptor, the pregnane X receptor (PXR; also known as steroid and xeno biotic receptor, or SXR) (Zhou et al. 2009b). "
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    ABSTRACT: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA and its analogues are present in environmental and human samples. Many endocrine-disrupting chemicals, including BPA, have been shown to activate the pregnane X receptor (PXR), a nuclear receptor that functions as a master regulator of xenobiotic metabolism. However, the detailed mechanism by which these chemicals activate PXR remains unknown. We investigated the mechanism by which BPA interacts with and activates PXR and examined selected BPA analogues to determine whether they bind to and activate PXR. Cell-based reporter assays, in silico ligand-PXR docking studies, and site-directed mutagenesis were combined to study the interaction between BPA and PXR. We also investigated the influence of BPA and its analogues on the regulation of PXR target genes in human LS180 cells. We found that BPA and several of its analogues are potent agonists for human PXR (hPXR) but do not affect mouse PXR activity. We identified key residues within hPXR's ligand-binding pocket that constitute points of interaction with BPA. We also deduced the structural requirements of BPA analogues that activate hPXR. BPA and its analogues can also induce PXR target gene expression in human LS180 cells. The present study advances our understanding of the mechanism by which BPA interacts with and activates human PXR. Activation of PXR by BPA may explain some of the adverse effects of BPA in humans.
    Environmental Health Perspectives 01/2012; 120(3):399-405. DOI:10.1289/ehp.1104426 · 7.03 Impact Factor
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