Endocrine Disruptors: Time to Act
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Recent decades have seen progress in the identification and quantification of a wide array of chemicals with endocrine-active properties. Exposure to these so-called endocrine-disrupting chemicals (EDCs) has been implicated in an increase in certain adverse health effects, and some new prospective birth cohort studies have yielded suggestive results on these exposure-effect relationships. Major research efforts have focused on the EDC exposure of women of child-bearing age, because of concerns about embryonic and fetal susceptibility to these chemicals. Investigations have shown that mothers and children are exposed to a complex mixture of compounds; therefore, studies on the health impact of EDC exposure should not be limited to the individual effects of single agents but should rather consider the cumulative effects of multiple chemicals. There is considerable political debate about the need for measures to reduce or avoid exposure to EDCs. While a tighter regulation of exposure to EDCs is being implemented, health professionals and public health practitioners should acquire knowledge of the problem, recognize exposure, and warn the general population about the health risks.
KeywordsEndocrine disruptors Adverse effects Risk assessment Prenatal exposure
The ever-growing use of chemicals in modern society has resulted in their increasing production and use, reaching global dimensions. Some chemicals, such as pesticides, are intentionally released into the environment, while others are released as the result of accidents and spills. Chemicals that are the by-products of manufacturing processes can also enter the environment through various pathways. Over recent decades, observations of the effects of exposure to some anthropogenic chemicals, mainly on wildlife, have increased public awareness of the risks they pose .
According to a recent update from the World Health Organization (WHO) (2013) , endocrine-disrupting chemicals (EDCs) are defined as chemicals with the capacity to modify hormonal balance and embryonic development and to promote adverse health effects on living organisms or on their offspring. EDCs are highly diverse, with different origins, structures, and functions . They can interfere with the endocrine system by mimicking the action of naturally produced hormones; by preventing the action of endogenous hormones; by altering the synthesis and function of hormone receptors; or by modifying the synthesis, transport, metabolism, or excretion of hormones . They can interfere with the effects of endogenous hormones by acting as receptor agonists or antagonists (or both, when acting as modulators), altering hormonal signaling and therefore the action of hormones. EDCs can also affect hormone concentrations indirectly by acting on signaling pathways that control hormone production or elimination [2, 3]. Finally, there is increasing scientific evidence that EDCs can affect the exposed organism, its offspring, and future generations through non-genomic modifications and/or epigenetic changes .
Human Exposure to EDCs
Biomonitoring studies have shown that humans are exposed to hundreds of EDCs. The lipophilicity and resistance to degradation of some EDCs, e.g., organochlorine pesticides or polybrominated diphenyl ethers (used as flame retardants), means that they accumulate in the fatty tissues of organisms after their release into the environment. Other EDCs to which humans are exposed daily, e.g., bisphenol A (from polycarbonate plastics), phthalates (softener in plastics), or some organophosphate pesticides, are rapidly metabolized and excreted but also contribute to the internal dose .
The impact of EDC exposure on human health strongly depends on the age at which it occurs. Thus, the effects of exposure in utero or during pre-puberty can be expected to differ from those of exposure during adulthood. Both embryos and neonates are highly sensitive to EDC exposure and suffer more severe adverse effects than do adults [6, 7]. Thus, exposure during development to EDCs at low doses can produce functional changes in gene expression and may lead to an increased risk of dysfunction and disease later in life, despite the absence of phenotypic changes observable at birth . Many EDCs can cross the placenta and enter the fetus during a highly critical window of vulnerability to their adverse effects [6, 7, 8]. Hence, the fetus can be exposed not only to persistent and bio-accumulated substances stored in the mother’s adipose tissue and mobilized during pregnancy but also to widespread EDCs [9, 10]. EDCs can also reach the newborn via maternal breast milk .
The endocrine disruption hypothesis fits well the paradigm of the fetal origin of disease, which suggests that interactions between the developing organism and the environment determine the risk of disease in adulthood. The original concept of the “fetal basis of adult disease” was changed to the “developmental origin of adult disease” and most recently to the “developmental origins of health and disease (DOHaD)”, given that adverse effects may emerge in childhood and adolescence, and health–disease represents a continuous spectrum of outcomes in response to risk factors .
The chemical analysis of human placentas has been proposed as an ideal method to investigate exposure of the mother–infant pair to EDCs, yielding data on the exposure of both mother and fetus with no need for an invasive procedure .
Prenatal Exposure to EDCs
Pregnancy is the time when exposure to EDCs can disrupt or interfere with the physiology of developing cells, tissues, and/or organs, leading to permanent adverse health effects to the exposed organism and future generations [14, 15]. Several population-based studies have found that virtually all pregnant women had measurable levels of different EDCs in their bodies [14, 15, 16]. Published data on EDC exposure during pregnancy have verified the presence of numerous chemical residues in different female human tissues. For example, in a population-based cohort study in Southern Spain that focused on prenatal environmental exposures in relation to growth, development, and health from early fetal life until childhood , organochlorine compounds (OCs), polychlorobiphenyls (PCBs), dioxins, furans, benzophenones, parabens, and bisphenols, among others, were present in placenta tissue [9, 10, 17, 18, 19, 20, 21].
Thus, the presence of 17 OCs (o,p′-DDT; p,p′-DDT; o,p′-DDD; p,p′-DDE; endosulfan-I and -II; endosulfan-diol, -sulfate, -lactone, and –ether; aldrin; dieldrin; endrin; lindane; hexachlorobenzene [HCB]; mirex and methoxychlor) was investigated in the INMA (INfancia y Medio Ambiente [Environment and Childhood] project) cohort. All placentas studied (n = 311) were positive for at least one OC, with a mean of eight residues per placenta (range 2–15 compounds). The most frequent compound was p,p′-DDE (96.2 %), with a mean value of 9.21 ng/g of placenta, followed by lindane (76.4 %), endosulfan-diol (63.2 %), o,p′-DDT (55.9 %), endosulfan-I (52.7 %), and endosulfan-ether (50.0 %). Around 98 % and 96 % of the samples, respectively, had detectable levels of at least one of the studied DDT and endosulfan isomers/metabolites [9, 17]. Further, more than half of the placentas (58.5 %; 182/311) were found to contain free bisphenol A (BPA) at concentrations ranging from 0.5 to 134.0 ng/g of placenta, suggesting exposure of the fetus to this EDC. BPA was also detected in the urine of mothers during the third trimester of pregnancy and in the urine of their children at the age of 4 years .
Exposure to four parabens and six benzophenones was also investigated in human placental tissue samples [18, 19]. Methyl-paraben was detected in 92 % (286/311) of analyzed samples and quantified in 91 % (283/311), at concentrations ranging from 0.1 to 22.1 ng/g placenta; ethyl-paraben was detected in 70.7 % (220/311) of the samples and quantified in 59.2 % (184/311) at concentrations of 0.2–12.8 ng/g placenta; propyl-paraben was detected in 78.1 % (243/311) of the samples and quantified in 70.1 % (218/311) at concentrations of 0.2–2.7 ng/g placenta; and butyl-paraben was detected in 30.2 % (94/311) of the samples and quantified in 18.3 % (57/311), at concentrations ranging from 0.2 to 1.6 ng/g placenta . Among the six benzophenones investigated, benzophenone-1, benzophenone-2, benzophenone-3, and benzophenone-8 were not detected in any of the placenta samples; 4-hydroxybenzophenone was detected in 49.8 % (155/311) and quantified in 47.6 % (148/311) of the samples, at concentrations ranging from 0.2 to 5.3 ng/g placenta; and benzophenone-6 was detected in 12.5 % (39/311) of the samples and quantified in 11.3 % (35/311), at concentrations ranging from 0.4 to 40.6 ng/g placenta .
Finally, the concentration of seven polychlorinated dibenzo-p-dioxins (PCDDs), ten dibenzofurans (PCDFs), four non-ortho PCBs (PCB-77, -81, -126, and -169), eight mono-ortho PCBs (PCB-105, -114, -118, -123, -156, -157, -167, and -189) and 12 dioxin-like [DL-] PCBs was also analyzed in placenta samples . All PCDD/F congeners tested, with the exception of 1,2,3,7,8,9-HxCDF, were found in all study samples. Toxic equivalent (TEQ) concentrations of PCDD/Fs and DL-PCBs were 6.9 pg WHO-TEQ/g lipid and 2.1 pg WHO-TEQ/g lipid, respectively, with the most abundant PCDD/F congeners being those with the longest half-lives .
The Complexity of EDC Risk Assessment
Risk assessment in the endocrine-disruption field is a highly complex task. For instance, dose-response assessment is usually based on the assumption of monotonic dose-response curves for almost all chemicals, with linear dose-response models predicting effects at low doses by extrapolation from effects at high doses . However, this model is not generally suitable for the study of EDCs, because their hormone-like behavior can generate non-monotonic (e.g., U-shaped or other non-linear) dose-response curves, in which effects can be more harmful at lower than at higher doses. This behavior is attributable to the complex dynamism that characterizes the occupation-saturation of the hormonal receptor [6, 23•]. Moreover, some EDCs can show a monotonic linear response when examined in a simple experimental test but can exhibit other response patterns in the presence of endogenous hormones; hence, their effects may depend on the hormonal status of an individual at the time of exposure . These characteristics, which seem unique to EDCs, make their study particularly challenging. Moreover, the action of EDCs on a given tissue may vary according to their isoform and the presence or abundance of specific receptors on the tissue. Hence, realistic risk estimations must take account of the hormonal pattern of individuals, the susceptibility of each tissue or organ, and the timing of exposure, because small variations can affect the functionality of the system if homeostatic mechanisms are not adequate [7, 8].
As shown above, mothers and their children are not exposed to a single chemical alone but rather to a complex mixture of compounds. Therefore, investigation of the impact on human health of EDC exposure should not be limited to the individual effects of single agents but should rather consider the cumulative effects of multiple chemicals [24, 25]. Several authors have pointed out that even the most comprehensive chemical analysis may only explain part of the biologically effective endocrine-disrupting potential evidenced in bioassays [26, 27]. For this reason, studies on environmental exposure during pregnancy and childhood have recommended the use of biomarkers to evaluate mixtures of EDCs in the organism as well as inter-individual variability . Thus, our research group developed the total effective xenoestrogen burden (TEXB) as a reliable biomarker of the cumulative exposure to mixtures of xenoestrogens in the organism, using a specific bioassay to establish the combined estrogenicity in different biological samples [26, 28]. TEXB is based on the proliferative effect on human breast cancer cells of human biological extracts, which has been applied to epidemiological studies in relation to the risk of developing several human diseases, including anomalies of sexual maturation in males, breast cancer, and type 2 diabetes [9, 29, 30]. In addition, an association has been found between higher prenatal TEXB levels and increased birth weight in males . The use of TEXB in placenta samples appears to be a reasonable strategy for assessing maternal exposure to xenoestrogens and for estimating exposure of the fetus, and it may represent a more useful approach than the study of individual chemical residues [9, 26].
Endocrine Disruptors and Human Diseases
Testicular Dysgenesis Syndrome (TDS)
Over the past few decades, most Western countries have reported an increase in male reproductive disorders, especially those related to TDS, including cryptorchidism (absence of one or both testes from the scrotum), hypospadias (abnormally placed urinary meatus), poor semen quality, and testicular cancer . Although the etiology of TDS is not known in most cases, it has been hypothesized that this rise is due not only to improvements in clinical detection but also to a combination of genetic and environmental factors, including exposure to mixtures of environmental pollutants [38, 39•].
Obesity and Diabetes
Once more, assessment of the effect of EDCs on obesity and diabetes is a highly complex task, given the other risk factors involved, e.g., diet and physical exercise (especially difficult to measure), and the need to evaluate of the effects of early life exposures to mixtures of EDCs on outcomes much later in life .
In parallel with the rise in obesity, the prevalence of type 2 diabetes worldwide is estimated to reach 4.4 % in 2030 (vs. 2.8 % in 2000) . This increasing trend has been attributed to a combination of genetic and environmental factors , and chronic exposure to low doses of EDCs has also been implicated. Thus, exposure to certain persistent organic pollutants (POPs) has been associated with an increased risk of the disease [52, 53, 54, 55, 56], including recent findings from our group reporting a significant association between the adipose tissue concentrations of certain POPs and the risk of type 2 diabetes in an adult population . Serum levels of POPs and/or PCBs have been positively associated with diabetes risk in cross-sectional and longitudinal studies and a meta-analysis [52, 53, 54, 55, 56], but the risks associated with individual POPs are not entirely consistent across studies.
Biomarkers based on hormonal activity have been developed for a more accurate quantification of exposure, allowing evaluation of the effects caused by cumulative exposure to a mixture of EDCs. In this regard, a statistically significant relationship was found between breast cancer risk and the combined effect of environmental xenoestrogens by applying a biomarker of exposure to assess the TEXB in human adipose tissue in a case–control study . Environmental estrogens were separated from endogenous estrogens, and the combined estrogenic effect due to the bioaccumulation of organohalogenated xenoestrogens was determined from its proliferative effect in the E-screen assay .
To add further complication to the issue, breast cancer starts to develop many years before the onset of symptoms, and chemicals should be measured at multiple developmental time points. The chemical burden can also vary as a function of changes in lifestyle. Hence, both chemical analyses and studies of chemical burden are warranted in follow-up studies of women exposed to multiple residues in order to elucidate the clinical significance of the distribution of residues at low and high doses in the same individual. These types of study are essential to address current uncertainties about the functionality of EDCs in human tissues [73, 74].
Public Policy Implications
There is considerable political debate about the need for measures to reduce or avoid exposure to EDCs, and this controversy has affected the progress of knowledge on endocrine disruption. Thus, implementation of an action plan developed by the European Parliament in 1999 was limited to the prohibition of phthalates in pacifiers/teethers/nipples and bisphenol A in polycarbonate baby bottles, based on the precautionary principle to protect children’s health. Our data show that Spanish children are in the top ranking of exposure to phthalates compared with other USA studies involving pregnant women , and we believe that the scientific evidence is adequate to support the implementation and extension of these preventive measures.
Growing demands for action to protect the public from EDCs led the Committee on Environment, Public Health and Food Safety of the European Parliament to propose a resolution, passed in 2012 [2012/2066(INI)], on the need to reduce human exposure to these chemicals, especially among the most vulnerable groups, taking into account the difficulty of establishing safe levels of exposure. It proposed improvements in the European regulation system – REACH – and the examination of all available scientific studies in a review of the risk-assessment process. As with REACH in the EU, a new chemicals policy in the USA has the potential to fuel global demand for safer substances and processes, increasing the incentive for research and development in green chemistry while improving human and environmental health . In addition, environmental health scientists have an essential role in identifying and addressing the research questions that will arise with the development of new EDC policies. Scientists and representatives of environmental organizations recently published a report on key scientific issues relevant to the identification of EDCs for use in different regulatory contexts . Some toxicologists involved with regulatory bodies, all editors of toxicology journals, recently declared in an open letter that the recommendations of the report were inadequate and that the current system of risk evaluation should be maintained . However, a large group of scientists reaffirmed, in an editorial responding to the letter, that there was already sufficient evidence to support further measures to reduce EDC exposure .
While awaiting the implementation of stricter regulation of exposure to EDCs, health professionals should be fully aware of this issue, recognizing exposure and advising the population about the health risks. It is also important for healthcare professionals to use their influence in the policy-making arena to ensure that emerging scientific findings are translated into prevention-oriented action on a large scale . It is time to act, identifying and reducing exposure to toxic environmental agents while addressing its consequences.
Increasing evidence supports the role of EDCs on human health. An important advance in recent years has been the increased number of prospective birth cohort studies revealing suggestive exposure-effect relationships. Consistent with the precautionary principle for reducing risk in the absence of causal evidence, the Royal College of Obstetricians and Gynecologists concluded, “Despite uncertainty surrounding the effect of common environmental chemicals, mothers should be made aware of the sources and routes of exposure, the potential risk to the baby and the important role that the mother can play in minimizing her baby’s chemical exposure” . Essential strategies for diminishing harmful EDC exposure and improving health outcomes are urgently needed.
This work was supported by grants from the Spanish Ministry of Health (FIS-PI11/00610); Instituto de Salud Carlos III (Red INMA G03/176 and CB06/02/0041); the EU Commission (QLK4-1999-01422, QLK4-2002-00603, and CONTAMED FP7-ENV-212502), the Consejería de Salud de la Junta de Andalucía (grant numbers 183/07 and 0675/10). The HUSC BioBank, integrated in the Andalusia Public Health System (SSPA) and the National Biobank Network, is financed by the Institute of Health Carlos III (project RD09/0076/00148), and the Regional Government of Andalucía.
Compliance with Ethics Guidelines
Conflict of Interest
Mariana F. Fernández, Marta Román, Juan Pedro Arrebola, and Nicolás Olea declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
This article contains data from studies with human subjects, some of them performed by the authors. All those studies followed the guidelines laid down in the Declaration of Helsinki and were approved by the Ethics Committee of the corresponding Institutions.
Papers of particular interest, published recently, have been highlighted as: • Of importance
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