Preface

This special issue summarizes key aspects of the state of knowledge regarding endocrine disruptors and their effect and suggests how this scientific information can affect regulatory and other legal efforts being considered both in the European Union (EU) and in the United States. Although much of the discussions included in this special issue is about bisphenol A (BPA), several lines of scientific enquiry apply to other endocrine disruptors. Its editors, Fabbri and Ricci, began this effort to determine whether dose–response relationships, both in the literature and through individual studies, could be identified so that policy and regulatory law would benefit from that form of causality formally to justify environmental and public health standard for exposure, possibly including cessation of exposure through bans. The scientific findings reported by key international researchers, as presented in this issue, suggest that this is not yet possible. However, it is becoming increasingly clear that endocrine disruptors create risks in ways that are uncommon in toxicology, a fact that is supported by epidemiologic results of different types. The policy dilemma that seemingly cannot be resolved—other than by policy fiat—is whether it is societally more appropriate to wait for dose–response relationships to be theoretically and experimentally confirmed or to reduce exposure through laws and regulations based on weak and contradictory evidence. Ricci addresses this problem in his article and suggests (that the formal answer can be found in probabilistic decision theoretic methods in which value of information and value of flexibility play a prominent role). Of course, political trade-offs go beyond those solutions, and the role of our work is to inform stakeholders and not supplant their role. The authors who have prepared articles for this special issue have focused on environmental health exposures and effects on a number of entities at risk, most notably animals and human studies.

In particular, Corrales and coauthors reviewed over 500 peer-reviewed articles as a means to understand the sources and sinks of BPA, including its bioaccumulation and the resulting wildlife and human exposures. New data are also added, filling some gaps in the available knowledge. The effect of those exposures appears to be stymied by incomplete information; nonetheless, despite the uncertainties, their arguments suggest that exposure to BPA is clearly dangerous and should be reduced. These authors also stress the usefulness of coordinating global sensing of environmental contaminants, through integrating environmental monitoring and specimen banking, thus achieving more robust environmental assessment and management programs.

Acconcia, Pallotini, and Marino provide an understanding of the molecular aspects of BPA dose-dependent exposure. Their review of the state of the regulatory aspects of BPA suggests a number of contradictions in part due to the different mechanisms through which BPA is known to be associated with adverse health effects in humans and other species. They review aspects of BPA’s binding to estrogen and androgen receptors and suggest that the key mechanism is its interference with estrogen receptors. Other effects are related to orphan receptors, thyroid hormone, pregnane X, and others. In conclusion, it is not clear what form of effects BPA causes, and thus the mechanisms of action remain elusive. These authors also review several additional mechanisms (eg, in vivo genetic and epigenetic deregulation), finding that these mechanisms are still unclear, although the indication appears to be that they may affect the onset of diseases in later life.

Negri-Cesi addresses the dose–response that may exist between BPA and brain developmental functions in humans and starkly conclude that such relationship is still “unfeasible,” given the current evidence generated by different protocols used by the researchers. Although much is understood, particularly from in vivo studies with rats and mice, different results from different routes of administration of BPA do not yield reliable dose–response relationships. This author provides an extensive review of most recent findings regarding the effect of BPA on brain functions, their mechanisms, the adverse effects on the central nervous system, development, reproduction, and other brain-related events. Thus, although dose–response is still elusive, the author appeals to the precautionary principle as a means to reduce exposure.

Mannelli and coauthors present in vitro models for toxicology in human pregnancy, extremely important since in vivo models cannot be used. They report examples of in vitro approaches that are informative about the effect of chemicals at the maternal–fetal interface and can give fruitful insights about the possible correlations between environmental pollutants and reproductive disorders. They also highlight how it is difficult to classify chemically induced alterations as adverse or nonadverse effects, given the dynamic and complex mechanisms responsible for blastocyst implantation and placenta development in the maternal uterus. The need for protecting both prenatal life and development of the fetus requires more studies and better biological tools, since chemicals present in daily used products, that is, BPA and para-nonylphenol (p-NP) have the potential to interfere with human pregnancy even at very low concentrations.

Alonso-Magdalena, Quesada, and Nadal key concerns are the effect of endocrine disruptors on metabolic disorders, namely, type 2 diabetes and obesity throughout an exposed individual’s life, from the fetal stage to adulthood. In particular, the data reviewed underline that prenatal exposure to low doses of BPA may cause adverse effects on outcomes, for example, increased body weight (obesogenic action), altered glucose homeostasis (diabetogenic action), or both (diabesogenic action). Their review of recent findings, from mechanistic to epidemiological, indicates that some of the evidence is correlative, but several of the mechanistic aspects remain unknown. Their work confirms what other authors in this special issue have reported, in particular that in vivo studies show adverse effects below the current regulatory dose rates in the United States (US Environmental Protection Agency [EPA] 50 μg /kg bw/day) and the EU (also 50 μg/kg bw/day but under recommendation be lowered by a factor of 10l; European Food Safety Agency [EFSA], 2014), albeit for different reasons. More mechanistic insides are, nonetheless, required in order to completely understand the molecular basis of the obesogenic, diabetogenic, and diabesogenic actions of BPA.

Obesity is a worldwide concern. Among other risk factors, such as diet and lack of exercise and television watching, obesity is causally associated with exposure to BPA, which is also known to result in increased incidence of type 2 diabetes and cardiovascular disease. As Bertoli, Leoni, and Battezzati discuss, causation remains problematic. For example, BPA is a obesogen that downregulates aspects of metabolism, the effectiveness of the endocrine hormonal system, and other mechanisms not only after birth but also in utero. Yet, that evidence has conflicts that have been attributed to the range of exposures used in in vitro and in vivo experiments. The authors also review epidemiological evidence regarding BPA and obesity and report that this endocrine disruptor, at low doses, increases the body mass index and waist size in children and adolescents. Similar results were found in adults. The conclusion from cross-sectional and prospective epidemiological studies is that these results may be due to confounding and biases, a general issue that often affects epidemiological studies.

Canesi and Fabbri’s main concerns are with the effect of BPA on vertebrate and invertebrate aquatic species. They report that BPA can have different mechanisms of action, a key factor in regulating exposure to endocrine disruptors. The range of adverse effects in vertebrate species ranges from reproductive to developmental, and it affects the thyroid, metabolism, and the immune system among others. In invertebrates, the effects range from increasing messenger RNA levels to questioning the effect of BPA on estrogen receptors, which is contrary to a widely held hypothesis, BPA also appears to affect embryogenesis. These authors review both the sources and the sinks for BPA, including landfills and wastewater treatment plants. Although they note that BPA both bio- and photodegrade, and the temporal window of exposure for aquatic species may be limited, they also suggest that, because BPA is constantly discharged into the aquatic environment, it becomes pseudo-persistent.

Through a review of their CD-1 mice study, Gioiosa and her coauthors underline that nonreproductive, sexually dimorphic behaviors are sensitive to endocrine disruption during critical periods of life and that sex differences represent a relevant issue when designing risk assessment studies. They also indicate that the early postnatal environment, including offspring lactational exposure to BPA, is a period during which there is high vulnerability to long-lasting effects on physiology (metabolic disruption and diseases development), brain development, and behavior. They conclude that the risks from BPA due to low dosages during development may be indicative of adverse effects in fetuses and human infants, although these adverse effects appear not to occur at higher doses. This finding suggests that monotonic dose–response models—the mainstay of environmental and human health risk assessments—may be inappropriate for endocrine disruptors. Nevertheless, the fact that nonmonotonic dose–response relationships do commonly occur in endocrinology has not been incorporated into the process of assessing risk of exposure to environmental chemicals, and the assessment of risk in response to chronic low-dose exposure to chemicals is determined by examining acute toxic effects of only a few very high doses. This demonstrates the urgent need for development of strategies for assessing the hazards posed by Endocrine Disruptive Chemicals (EDCs) that are consistent with the current endocrinology principles.

Ricci reviews the state of science policy in the United States and the EU finding a decoupling between the scientific aspects of causation and the way the regulatory law operates. He finds that other aspects of civil law, such as toxic torts law, prevent the legal system from compensating individuals who are at risk from exposure to endocrine disruptors because of an almost complete reliance on epidemiologic studies. He also finds that regulatory law, both in the United States and in the EU, tends to reduce public exposure through reducing exposures even when causation is not only problematic but can be beset by contradictory findings, by appeal to only one aspect of precaution, and bypassing incomplete causation but avoiding considering risk–cost– benefit balancing.

In conclusion, the special issue provides several new contributions toward understanding the interactions between endocrine disruptors and living organisms, based on molecular and cellular mechanisms and how those may explain effects observed on apical endpoints. The special issue also highlights how BPA may act through unconsolidated toxicological pathways and points out how those have to be taken into account in risk analysis. To the extent that risk analysis supports decision making, this special issue develops salient aspects of EU and US laws regarding how the setting of regulations and guidelines uses scientific evidence and how reviewing courts scrutinize risk-based actions taken by the Agencies or Authorities whose charge is to develop them.