Concerns regarding Endocrine Disrupting Chemicals

New Life Health Ventures is very concerned about Endocrine Disrupting Chemicals (EDCs) be they pharmaceuticals or environmental chemicals.  We believe and hypothesize  that the peptide relaxin can be impacted by EDCs and altered and that this can have inner generational effects- the parent can be damaged and the damaged can be passed on to the fetus or child.

New Life Health Ventures has found American Researchers and Practioners to be largely ignorant and disinterested in developing a more comprehensive understanding of the human body- the discoveries of relaxin and developing an understanding of harmful chemicals, isolating them and protecting people and wild life from them.  These two realities serve to make many if not most research studies for mental health and endocrine realities negligent and faulty.

We are not alone in our concerns.  The World Health Organization (WHO) has found that Endocrine disrupting chemicals (EDC) such as some pesticides are found in everyday items and can leach into our environment, sometimes remaining for a long time. Research has found connections between these chemicals and implications for health, particularly of vulnerable populations such as children and women.

EDCs are a growing global concern. Following a Global assessment in 2002, WHO and the United Nations Environment Programme collaborated to publish the State of the science of endocrine disrupting chemicals in 2012. This report presents the latest scientific findings, conclusions and key concerns for human health. WHO is currently working on an update of this report.

WHO is working on EDCs in collaboration with experts globally to:

• spread awareness and update knowledge
• facilitate research on child health effects
• develop materials to prevent and reduce exposures during pregnancy and childhood
• develop and update key information and capacity training materials for health care workers.

EDCs are a particular risk facing children today. Children are exposed to low doses and mixtures of EDCs, which can have different effects depending upon dose and other chemicals present. Exposure during pregnancy and early childhood may impact the health and development of a child for the rest of their life. Preventing exposure is essential.

We believe it is reasonable to hypothesize that EDCs play a role in the increase in gender dysmorphia and may in other ways alter normal transition during puberty for many.  We advocate greater testing and leading all delicate discussions with the very real possibility that EDCs may be in play.

Please visit the WHO Information on EDCs and Child Health

A Direct Quote of the WHO 2012 Study is as follows:

The Strategic Approach to International Chemicals Management (SAICM) was established by the International Conference on Chemicals Management (ICCM) in February 2006, with the overall objective to achieve the sound management of chemicals throughout their life cycle so that, by 2020, chemicals are used and produced in ways that minimize significant adverse effects on human health and the environment. SAICM recognizes that risk reduction measures need to be improved to prevent the adverse effects of chemicals on the health of children, pregnant women, fertile populations, the elderly, the poor, workers and other vulnerable groups and susceptible environments.

It states that one measure to safeguard the health of women and children is the minimization of chemical exposures before conception and through gestation, infancy, childhood and adolescence. SAICM also specifies that groups of chemicals that might be prioritized for assessment and related studies, such as for the development and use of safe and effective alternatives, include chemicals that adversely affect, inter alia, the reproductive, endocrine, immune or nervous systems. A resolution to include EDCs as an emerging issue under SAICM was adopted in September 2012 by ICCM at its third session. EDCs represent a challenge, as their effects depend on both the level and timing of exposure, being especially critical when exposure occurs during development. They have diverse applications, such as pesticides, flame retardants in different products, plastic additives and cosmetics, which may result in residues or contaminants in food and other products. Therefore, EDCs may be released from the products that contain them.

The protection of the most vulnerable populations from environmental threats is a key component of the Millennium Development Goals. As the challenge in meeting the existing goals increases, with work under way in developing countries to overcome traditional environmental threats while dealing with poverty, malnutrition and infectious disease, emerging issues should be prevented from becoming future traditional environmental threats. Endocrine disruption is a challenge that must continue to be addressed in ways that take into account advances in our knowledge. UNEP and WHO, in collaboration with a working group of international experts, are taking a step forward by developing these documents on endocrine disruptors, including scientific information on their impacts on human and wildlife health and key concerns for decision-makers and others concerned.

This work concluded that scientific knowledge at that time provided evidence that certain effects observed in wildlife can be attributed to chemicals that function as endocrine disrupting chemicals (EDCs); that the evidence of a causal link was weak in most cases and that most effects had been observed in areas where chemical contamination was high; and that experimental data supported this conclusion. The document further concluded that there was only weak evidence for endocrine-related effects in humans. Uncertainties regarding global endocrine disrupting effects were put forward; simultaneously, concern was expressed that endocrine disruption may affect developmental processes if exposure occurs during early life stages.

Almost no data regarding endocrine-related effects were available for chemicals other than those defined as persistent organic pollutants (POPs) according to the Stockholm Convention on Persistent Organic Pollutants: polychlorinated biphenyls (PCBs), dioxins and dichlorodiphenyltrichloroethane (DDT). Even for these chemicals, the data gaps were obvious for parts of the world other than western Europe, North America and Japan. The IPCS (2002) document finally concluded that there was a need for broad, collaborative and international research initiatives and presented a list of research needs. Since the start of this century, intensive scientific work has improved our understanding of the impacts of EDCs on human and wildlife health.

Scientific reviews published by, for example, the Endocrine Society (Diamanti-Kandarakis et al., 2009), the European Commission (Kortenkamp et al., 2011) and the European Environment Agency (2012) show the scientific complexity of this issue. These documents implicate EDCs as a concern to public and wildlife health. In addition, the European Society for Paediatric Endocrinology and the Pediatric Endocrine Society have put forward a consensus statement calling for action regarding endocrine disruptors and their effects (Skakkebaek et al., 2011). Now, in 2012, the United Nations Environment Programme (UNEP) and WHO present an update of the IPCS (2002) document, entitled State of the Science of Endocrine Disrupting Chemicals—2012.

This document provides the global status of scientific knowledge on exposure to and effects of EDCs. It explains, in the first chapter, what endocrine disruption is all about, and then it discusses in detail, in 12 sections in the second chapter, endocrine disrupting effects in humans and wildlife. The work is based on the fact that endocrine systems are very similar across vertebrate species and that endocrine effects manifest themselves independently of species. The effects are endocrine system related and not necessarily species dependent. Effects shown in wildlife or experimental animals may also occur in humans if they are exposed to EDCs at a vulnerable time and at concentrations leading to alterations of endocrine regulation.

Of special concern are effects on early development of both humans and wildlife, as these effects are often irreversible and may not become evident until later in life. The third and final chapter of this document discusses exposure of humans and wildlife to EDCs and potential EDCs. Key concerns

• Human and wildlife health depends on the ability to reproduce and develop normally. This is not possible without a healthy endocrine system.
• Three strands of evidence fuel concerns over endocrine disruptors: ◦ the high incidence and the increasing trends of many endocrine-related disorders in humans; ◦ observations of endocrine-related effects in wildlife populations; viii ◦ the identification of chemicals with endocrine disrupting properties linked to disease outcomes in laboratory studies.
• Many endocrine-related diseases and disorders are on the rise.

◦ Large proportions (up to 40%) of young men in some countries have low semen quality, which reduces their ability to father children.

 ◦ The incidence of genital malformations, such as non-descending testes (cryptorchidisms) and penile malformations (hypospadias), in baby boys has increased over time or levelled off at unfavourably high rates.

◦ The incidence of adverse pregnancy outcomes, such as preterm birth and low birth weight, has increased in many countries.

◦ Neurobehavioural disorders associated with thyroid disruption affect a high proportion of children in some countries and have increased over past decades.

◦ Global rates of endocrine-related cancers (breast, endometrial, ovarian, prostate, testicular and thyroid) have been increasing over the past 40–50 years.

◦ There is a trend towards earlier onset of breast development in young girls in all countries where this has been studied. This is a risk factor for breast cancer.

◦ The prevalence of obesity and type 2 diabetes has dramatically increased worldwide over the last 40 years. WHO estimates that 1.5 billion adults worldwide are overweight or obese and that the number with type 2 diabetes increased from 153 million to 347 million between 1980 and 2008.

• Close to 800 chemicals are known or suspected to be capable of interfering with hormone receptors, hormone synthesis or hormone conversion. However, only a small fraction of these chemicals have been investigated in tests capable of identifying overt endocrine effects in intact organisms.

◦ The vast majority of chemicals in current commercial use have not been tested at all. ◦ This lack of data introduces significant uncertainties about the true extent of risks from chemicals that potentially could disrupt the endocrine system.

• Human and wildlife populations all over the world are exposed to EDCs. ◦ There is global transport of many known and potential EDCs through natural processes as well as through commerce, leading to worldwide exposure.

Animals have an impact on current practice in toxicological testing and screening. Instead of solely studying effects of exposures in adulthood, the effects of exposures during sensitive windows in fetal development, perinatal life, childhood and puberty require careful scrutiny.

• Worldwide, there has been a failure to adequately address the underlying environmental causes of trends in endocrine diseases and disorders.

◦ Health-care systems do not have mechanisms in place to address the contribution of environmental risk factors to endocrine disorders. The benefits that can be reaped by adopting primary preventive measures for dealing with these diseases and disorders have remained largely unrealized.

• Wildlife populations have been affected by endocrine disruption, with negative impacts on growth and reproduction. These effects are widespread and have been due primarily to POPs. Bans of these chemicals have reduced exposure and led to recovery of some populations.

◦ It is therefore plausible that additional EDCs, which have been increasing in the environment and are of recent concern, are contributing to current population declines in wildlife species. Wildlife populations that are also challenged by other environmental stressors are particularly vulnerable to EDC exposures.

• Internationally agreed and validated test methods for the identification of endocrine disruptors capture only a limited range of the known spectrum of endocrine disrupting effects. This increases the likelihood that harmful effects in humans and wildlife are being overlooked.

◦ For many endocrine disrupting effects, agreed and validated test methods do not exist, although scientific tools and laboratory methods are available.

◦ For a large range of human health effects, such as female reproductive disorders and hormonal cancers, there are no viable laboratory models. This seriously hampers progress in understanding the full scale of risks.

• Disease risk due to EDCs may be significantly underestimated. ◦ A focus on linking one EDC to one disease severely underestimates the disease risk from mixtures of EDCs. We know that humans and wildlife are simultaneously exposed to many EDCs; thus, the measurement of the linkage between exposure to mixtures of EDCs and disease or dysfunction is more physiologically relevant. In addition, it is likely that exposure to a single EDC may cause disease syndromes or multiple diseases, an area that has not been adequately studied.
• An important focus should be on reducing exposures by a variety of mechanisms. Government actions to reduce exposures, while limited, have proven to be effective in specific cases (e.g. bans and restrictions on lead, chlorpyrifos, tributyltin, PCBs and some other POPs). This has contributed to decreases in the frequency of disorders in humans and wildlife.
• Despite substantial advances in our understanding of EDCs, uncertainties and knowledge gaps still exist that are too important to ignore. These knowledge gaps hamper progress towards better protection of the public and wildlife. An integrated, coordinated international effort is needed to define the role of EDCs in current declines in human and wildlife health and in wildlife populations. x General aspects on endocrine disruption (chapter 1) The present document uses the same definitions of EDCs and potential EDCs that were developed in IPCS (2002): “An endocrine disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations”; and “A potential endocrine disruptor is an exogenous substance or mixture that possesses properties that might be expressed to lead to endocrine disruption in an intact organism, or its progeny, or (sub) populations”. In addition to the key concerns presented above, the most relevant main messages from chapter 1 are presented below:

♦ What is endocrine disruption all about? Some endocrine disruptors can act directly on hormone receptors as hormone mimics or antagonists. Others can act directly on any number of proteins that control the delivery of a hormone to its normal target cell or tissue. ♦ The affinity of an endocrine disruptor to a hormone receptor is not equivalent to its potency. Chemical potency on a hormone system is dependent upon many factors.

♦ Endocrine disruptors produce non-linear dose– response curves both in vitro and in vivo, by a variety of mechanisms.

♦ Environmental chemicals can exert endocrine disrupting activity on more than just estrogen, androgen and thyroid hormone action. Some are known to interact with multiple hormone receptors simultaneously.

♦ Sensitivity to endocrine disruption is highest during tissue development; developmental effects will occur at lower doses than are required for effects in adults.

♦ Testing for endocrine disruption must encompass the developmental period and include lifelong follow-up to assess latent effects.

 ♦ Endocrine disruption represents a special form of toxicity, and this must be taken into consideration when interpreting the results of studies on EDCs or when designing studies to clarify the effects of EDCs and quantifying the risks to human and wildlife health. Over the last 10 years, it has been established that endocrine disruptors can work together to produce additive effects, even when combined at low doses that individually do not produce observable effects. Evidence for endocrine disruption in humans and wildlife (chapter 2) Over the last decade, scientific understanding of the relationship between exposure to endocrine disruptors and health has advanced rapidly. There is a growing concern that maternal, fetal and childhood exposure to EDCs could play a larger role in the causation of many endocrine diseases and disorders than previously believed. This is supported by studies of wildlife populations and of laboratory animals showing associations between exposure to EDCs and adverse health effects and by the fact that the increased incidence and prevalence of several endocrine disorders cannot be explained by genetic factors alone. Epidemiological studies to date have explored quite narrow hypotheses about a few priority pollutants, without taking account of combined exposures to a broader range of pollutants. The main messages for each endocrine disease or disorder described in chapter 2 are presented below, focusing on advances in knowledge and understanding since publication of the IPCS (2002) report. Female reproductive health

♦ Increased understanding of endocrine pathways governing female reproductive processes suggests that a role for EDCs in the multicausality of female reproductive dysfunction is biologically plausible.

♦ There is limited and conflicting experimental and epidemiological evidence to support a role for EDCs in advancing puberty and breast development and in causing fibroids (phthalates) and endometriosis (PCBs, phthalates and dioxins) and almost no evidence for causation of polycystic ovary syndrome or infertility; however, few studies have examined chemical causation of these diseases directly, and very few chemicals have been investigated.

♦ Historically high incidences of fibroids have also occurred in seal populations in the Baltic Sea and have been associated with exposure to contaminants (particularly PCBs and organochlorine pesticides). Recovery of these populations is now occurring, following a decline in the environmental concentrations of these chemicals. More evidence now exists that reduced reproductive success in female birds, fish and gastropods is related to exposure to PCBs, organochlorine pesticides, tributyltin and dioxins. As exposure to these EDCs decreased, adverse reproductive effects in wild populations also decreased.

♦ There is more evidence from laboratory studies now than in 2002 that chemical exposures can interfere with endocrine signalling of pubertal timing, fecundity and fertility and with menopause. xi

♦ There are many gaps in our knowledge of endocrine disruption of the female reproductive system. Many of the mechanisms are poorly understood, and the number of chemicals that have been investigated is limited.

♦ There are many gaps in the available chemical test methods for screening chemicals for endocrine disrupting effects on female reproduction. Regulatory tests for many wildlife taxa are currently not developed, and the endocrine end-points measured in mammalian assays are sometimes not adequate to detect possible roles of EDCs in inducing many of the female reproductive disorders and diseases described here. Male reproductive health

♦ In comparison with 2002, the incidence of testicular cancer has further increased in the European countries in which it has been carefully studied.

♦ Although geographical differences exist, semen quality has declined in some countries; 20–40% of young men in the general population of Denmark, Finland, Germany, Norway and Sweden have sperm counts in the subfertile range.

♦ Decreases in semen quality reported in Scandinavian studies parallel increases in the incidence of both genital abnormalities in babies and testis germ cell cancer in men in the same areas over the last 60 years. The occurrence of cryptorchidism at birth is associated with a 5-fold increased risk of testicular cancer and with impaired semen quality and subfecundity.

♦ Several epidemiological studies show weak associations between cryptorchidism in sons and exposure of their mothers to DES, paracetamol, mixtures of PBDEs or unknown pesticides during pesticide application. No associations have been found with individual pesticides, underlining the importance of including mixtures assessment in epidemiological and laboratory investigations. Studies have not identified associations with PCBs or with DDT/DDE.

♦ High accidental exposures to PCBs during fetal development or to dioxins in childhood increase the risk of reduced semen quality in adulthood. With the exception of these studies, there are no data sets that include information about fetal EDC exposures and adult measures of semen quality. No studies have been performed to explore the potential link between fetal EDCs and the risk of testicular cancer occurring 20–40 years later.

♦ Limited evidence suggests a slightly increased risk of hypospadias or of reduced semen quality associated with exposure to mixtures of endocrine disrupting pesticides. Limited evidence also suggests links between maternal phthalate exposure and reduced anogenital distance (a proxy for reduced semen quality) in baby boys. For most chemicals, potential associations between fetal exposure and childhood or adult male reproductive health have not been studied.

♦ An animal model for aspects of testicular dysgenesis syndrome has been established in the rat and shows an interrelationship between testicular dysgenesis and exposure to some EDCs during the fetal male programming window. There is now a mechanism demonstrated in the rat by which irreversible disorders of the male reproductive tract can be caused.

♦ Exposures to several anti-androgenic pesticides have been shown to induce cryptorchidism, hypospadias and reduced semen quality in rodent experiments and are also often linked to shortened anogenital distance.

♦ Not all effects seen in the rat appear across species, and vice versa. Recent data show that effects of phthalates in the rat are not seen in the mouse or in human testis studied in culture. For bisphenol A (BPA), the human testis model is more sensitive to toxic effects than the rat model. ♦ With the exception of testicular germ cell cancers, which are logistically difficult to detect, symptoms of androgen deficiency and estrogen exposure occur in a variety of wildlife species in both urban and rural environments and have been linked to exposure to chemicals in a limited number of species in some areas.

 ♦ The feminizing effects of estrogenic chemicals from sewage effluents on male fish were first reported in the 1990s and have now been seen in many countries and in several species of fish, indicating that this is a widespread phenomenon. Feminized (intersex) male fish have reduced sperm production and reduced reproductive success.

♦ The suite of effects seen in wildlife can be reproduced in laboratory studies in which experimental animals are exposed to EDCs. Sex ratio

♦ EDC-related sex ratio imbalances, resulting in fewer male offspring in humans, do exist (e.g. in relation to dioxin and 1,2-dibromo-3-chloropropane), although the underlying mechanisms are unknown. The effects of dioxin on sex ratio are now corroborated by results obtained in the mouse model.

♦ EDC-related sex ratio imbalances have been seen in wild fish and molluscs, and the effects of EDCs on sex ratios in some of these species are also supported by laboratory evidence. xii Thyroid-related disorders

♦ Compared with 2002, increased but still limited evidence exists showing associations between thyroidrelated disorders and chemical exposures. There is, however, very little direct evidence that effects on thyroid hormone action mediate these associations. There is currently no direct approach to test this hypothesis on human populations.

♦ Some epidemiological studies report associations between chemical exposures (PCBs, PBDEs, phthalates, BPA and perfluorinated chemicals) and thyroid function, including in pregnant women, but few of these report associations with thyroid measures in the cord blood of their offspring or with abnormal function in these offspring.

♦ Laboratory experiments with rodents show that there are many chemicals that can interfere with thyroid function. For example, exposure to PCBs clearly reduces serum thyroid hormone levels in rodents.

♦ Similarly, there are chemicals that can interfere directly with thyroid hormone action in a manner that will not be captured by measuring serum hormone levels only.

♦ The variability of effects seen is interpreted by some to indicate that there is no convincing evidence that chemicals can interfere with thyroid hormone action in humans.

♦ Evidence of relationships between exposure to chemicals and thyroid hormone disruption in wildlife species has increased in the last decade, especially in relation to exposure to the flame retardant PBDEs and PCBs, but other chemicals are inadequately studied.

♦ The strength of evidence supporting a role for EDCs in disrupting thyroid function in wildlife adds credence to the hypothesis that this could occur in humans.

♦ Thyroid disruption is acknowledged to be poorly addressed by the chemical tests currently listed in the Organisation for Economic Co-operation and Development conceptual framework. Genetic lines of mice are now widely available that could help clarify the mechanisms by which chemical exposures can interfere with thyroid hormone action. Neurodevelopmental disorders in children and wildlife

♦ There are some strong data sets (e.g. for PCBs, lead and methylmercury) showing that environmentally relevant developmental exposures to these EDCs and potential EDCs have caused cognitive and behavioural deficits in humans.

♦ Sufficient data indicate that in utero exposure to EDCs also affects cognition in animal studies, and limited data indicate that sexually dimorphic behaviours are also affected.

♦ Studies of exposed wildlife provide important information on exposure levels, early and subclinical effects and the clinical neurotoxicity of EDCs, because the mechanisms, underlying effects and outcomes of exposures are often similar to those in humans. Data showing effects on growth, development and behaviour in wildlife exist for some PCBs and mercury, but are sparse or non-existent for other EDCs.

♦ Since 2002, increased evidence supports the involvement of thyroid hormone mechanisms in neurodevelopmental disorders in humans and wildlife and the sensitivity of embryonic and postnatal development to EDCs when compared with adulthood.

♦ Severe thyroid hormone deficiency causes severe brain damage. Moderate (25%) or even transient insufficiency of thyroxine during pregnancy is also associated with reduced intelligence quotient, ADHD and even autism in children.

♦ Chemical testing strategies do not routinely require evaluation of the ability of a chemical to produce developmental neurotoxic effects in a pre-market setting. Hormone-related cancers

♦ The increase in incidence of endocrine-related cancers in humans cannot be explained by genetic factors; environmental factors, including chemical exposures, are involved, but very few of these factors have been pinpointed.

♦ For breast, endometrial, ovarian and prostate cancers, the role of endogenous and therapeutic estrogens is well documented; this makes it biologically plausible that xenoestrogens might also contribute to risks. However, chemicals shown to be associated with breast (dioxins, PCBs and solvents) or prostate (unspecified agricultural pesticides, PCBs, cadmium and arsenic) cancer either do not have strong estrogenic potential or are unspecified. The possibilities of involvement of EDCs in ovarian and endometrial cancers have received little attention.

♦ For thyroid cancer, there are indications of weak associations with pesticides and 2,3,7,8-tetrachlorodibenzo-p-dioxin, but there is no evidence that hormonal mechanisms are involved.

♦ Models of hormonal cancers are not available for regulatory testing. This makes the identification xiii of hormonal carcinogens very difficult and forces researchers to rely on epidemiological studies. However, epidemiological studies cannot easily pinpoint specific chemicals and can identify carcinogenic risks only after the disease has occurred.

♦ Similar types of cancers of the endocrine organs, particularly reproductive organs, are also found in wildlife species (several species of marine mammals and invertebrates) and in domestic pets. In wildlife, endocrine tumours tend to be more common in animals living in polluted regions than in those inhabiting more pristine environments. Adrenal disorders in humans and wildlife

♦ Experimental data and data from exposed wildlife populations suggest that both the hypothalamic– pituitary–adrenal (HPA) axis and the adrenal gland are targets for endocrine disruption caused by pollutants at environmentally relevant exposure concentrations; for example, adrenocortical hyperplasia is found in Baltic Sea seals exposed to a mixture of DDT and PCBs and their methyl sulfone metabolites. Despite this fact, and compared with other endocrine axes, the HPA axis has so far gained relatively little attention in endocrine disruptor research.

♦ Developing organs are particularly sensitive to alterations in hormone levels, and exposure to chemicals during critical windows of development may cause irreversible effects on the adrenal glands that may not be expressed until adulthood. Recent experimental data suggest that environmentally relevant exposures to pollutants (PCBs) affect development of the fetal adrenal cortex and the function of the HPA axis and induce delayed effects in the response to stress in animal models.

♦ For the great majority of chemicals, there is no evidence for effects of exposures on adrenal function, nor have there been any in vivo studies to test for this. A variety of chemicals and mixtures have, however, been shown to cause effects in vitro (in the H295R cell line). Bone disorders

♦ Limited studies indicate that accidental poisoning of humans with hexachlorobenzene, PCBs and DDT caused bone disorders, and a plausible, although not proven, endocrine mechanism for these effects has been proposed.

♦ Epidemiological studies on humans also show a relationship between exposure to endocrine disrupting POPs and decreased bone mineral density or increased risk of bone fractures. Metabolic disorders

♦ Obesity, diabetes and metabolic syndrome are due to disruption of the energy storage–energy balance endocrine system and thus are potentially sensitive to EDCs.

♦ Exposures of animal models to a variety of chemicals during early development have been shown to result in weight gain, revealing the possibility of an origin for obesity early in development. Because they are disrupting many components of the endocrine system involved in controlling weight gain (adipose tissue, brain, skeletal muscle, liver, pancreas and gastrointestinal tract), these chemicals constitute a new class of endocrine disruptors called “obesogens”.

♦ Obesity is also correlated with type 2 diabetes, and chemicals that have been shown to cause obesity in animal models also result in altered glucose tolerance and reduced insulin resistance.

♦ There are no compelling animal data linking chemical exposures with type 1 diabetes, although some chemicals can affect the function of insulinproducing beta cells in the pancreas, including BPA, PCBs, dioxins, arsenic and phthalates. Many of these chemicals are also immunotoxic in animal models, and so it is plausible that they could act via both immune and endocrine mechanisms to cause type 1 diabetes.

♦ Limited epidemiological data exist to support the notion that EDC exposure during pregnancy can affect weight gain in infants and children. Limited epidemiological data show that adult exposures to some EDCs (mainly POPs, arsenic, BPA) are associated with type 2 diabetes, but there are no data for type 1 diabetes, there is insufficient evidence of endocrine mechanisms and there is insufficient study of this area in general. Immune function and diseases in humans and wildlife

♦ It is clear from both laboratory data and human and wildlife samples that EDCs can play a role in the development of immune-related disorders and are at least partially responsible for their rise in recent years.

♦ Since 2002, molecular mechanisms connecting a variety of nuclear receptors to NF-κB (one of the master regulators of inflammation and immunity) have been elucidated, and developmental immunotoxicity studies link compounds such as DES and the phytoestrogen genistein to postnatal immune disorders. Estrogen exposure has been shown to cause prostate inflammation, and BPA caused allergic sensitization, antibody production and type 2 helper T cell immune responses. xiv

♦ Systemic inflammation, immune dysfunction and immune cancers such as lymphoma and leukaemia in humans have been associated with EDC exposures. These chemicals may exert their effects through nuclear receptor signalling pathways that have wellestablished ties with the immune system through crosstalk with inflammatory pathways.

♦ There are good epidemiological data associating exposure to polycyclic aromatic hydrocarbons, PCBs and other persistent POPs with autoimmune thyroid disease, exposure to phthalates and dioxins with endometriosis and allergies, and exposure to phthalates with asthma and other airway disorders. Endocrine mechanisms are not, however, clear.

♦ Together, these new insights stress a critical need to better understand how EDCs affect normal immune function and immune disorders and how windows of exposure may affect disease incidence (particularly for childhood respiratory diseases). Population declines

♦ Wildlife species and populations continue to decline worldwide. This is due to a number of factors, including overexploitation, loss of habitat, climate change and chemical contamination.

♦ Given our understanding of EDCs and their effects on the reproductive system, it is extremely likely that declines in the numbers of some wildlife populations (raptors, seals and snails) have occurred because of the effects of chemicals (DDT, PCBs and tributyltin, respectively) on these species. The evidence for EDCs as a cause of these population declines has increased now relative to 2002, due to recoveries of these populations following restrictions on the use of these chemicals.

♦ EDCs in modern commerce with mechanisms of action similar to those of the endocrine disrupting POPs are suspected to also be a factor contributing to declines seen in wildlife species today. Demonstrating a clear link between endocrine effects in individuals and population declines or other effects will always be challenging, because of the difficulty in isolating effects of chemicals from the effects of other stressors and ecological factors. An endocrine mechanism for current wildlife declines is probable, but not proven.

♦ In spite of concerns about rising human populations on a global scale, numerous industrialized countries have fertility rates well below replacement levels. It has generally been accepted that socioeconomic factors play a role in these changes. It is plausible that widespread poor semen quality and subfertility levels also contribute to this trend; however, this has not been explored systematically. Human and wildlife exposures to EDCs (chapter 3) There is far more knowledge on exposure to EDCs and potential EDCs today compared with 10 years ago. This applies to the diversity of chemicals being implicated as EDCs and to the exposure routes and levels in humans and wildlife. As examples, brominated flame retardants were mentioned only briefly and perfluorinated compounds not at all when the IPCS document on EDCs was prepared 10 years ago (IPCS, 2002). In addition to these, there are now many more EDCs being found in both humans and wildlife. The most relevant main messages regarding exposure to EDCs follow:

♦ Unlike 10 years ago, it is now better understood that humans and wildlife are exposed to far more EDCs than just POPs. However, only a fraction of the potential EDCs in the environment are currently known.

♦ EDCs are chemically diverse, are primarily manmade chemicals and are used in a wide range of materials and goods. EDCs are present in food, nature (wildlife) and human beings. They can also be formed as breakdown products from other anthropogenic chemicals in the environment and in humans, wildlife and plants.

♦ Humans and wildlife are exposed to multiple EDCs at the same time, and there is justifiable concern that different EDCs can act together and result in an increased risk of adverse effects on human and wildlife health.

♦ Right now, only a narrow spectrum of chemicals and a few classes of EDCs are measured, making up the “tip of the iceberg”. More comprehensive assessments of human and wildlife exposures to diverse mixtures of EDCs are needed. It should be a global priority to develop the capacities to measure any potential EDCs. Ideally, an “exposome”, or a highly detailed map of environmental exposures that might occur throughout a lifetime, should be developed.

♦ Exposures to EDCs occur during vulnerable periods of human and wildlife development—from fertilization through fetal development and through nursing of young offspring—which raises particular concern.

♦ New sources of exposure to EDCs, in addition to food, have been identified and include indoor environments and electronics recycling and dumpsites (the latter being issues of particular concern for developing countries and countries with economics in transition). Children can have higher exposures due to their handto-mouth activities and higher metabolic rate. xv

♦ Not all sources of exposure to EDCs are known because of a lack of chemical constituent declarations for materials and goods.

♦ Spatial and temporal monitoring is critical for understanding trends and levels of exposure. This monitoring should include tissues from both humans and wildlife (representing a range of species) as well as water or other environmental compartments to capture the less persistent EDCs.

♦ Levels in humans and wildlife are related to how much a chemical is used. Bans on several POPs have led to declines in environmental levels and human body burdens. In contrast, there are increasing levels of some newer EDCs, such as perfluorinated alkyl compounds and replacements for banned brominated flame retardants.

♦ There is global transport of EDCs through natural processes (ocean and air currents) as well as through commerce, leading to worldwide exposure of humans and wildlife to EDCs. Concluding remarks EDCs have the capacity to interfere with tissue and organ development and function, and therefore they may alter susceptibility to different types of diseases throughout life. This is a global threat that needs to be resolved. Progress We are beginning to understand the importance of certain events during development and throughout the lifespan that interact with genetic background to increase susceptibility to a variety of diseases. It is clear that a large number of all non-communicable diseases have their origin during development. It is also clear that one of the important risk factors for disease is exposure to EDCs during development.

Exposure to EDCs during development can, as demonstrated in animal models and in an increasing number of human studies, result in increased susceptibility to, and incidence of, a variety of diseases. These include some of the major human diseases that are increasing in incidence and prevalence around the world. The incidence of these diseases and dysfunctions is increased at current levels of exposure to EDCs in normal populations. It is also clear from human studies that we are exposed to perhaps hundreds of environmental chemicals at any one time. It is now virtually impossible to identify an unexposed population around the globe. There is an increasing burden of disease across the globe in which EDCs are likely playing an important role, and future generations may also be affected. There have been clear benefits for human and wildlife health from the declining use of these chemicals. Government actions to reduce exposures, while limited, have proven to be effective in specific cases (e.g. bans and restrictions on lead, chlorpyrifos, tributyltin, PCBs and some other POPs). This has contributed to decreases in the frequency of disorders in humans and wildlife.

The advances in our understanding of EDCs have been based mainly on information derived from studies in developed regions. There is still a major lack of data from large parts of the world, in particular from Africa, Asia and Central and South America. Future needs Better information on how and when EDCs act is needed to reduce exposures during development and prevent disease from occurring. A clear example of the success of primary prevention through exposure control is lead. We have identified the following needs to take advantage of current knowledge to improve human and wildlife health by prevention of environmentally induced diseases. A. Strengthening knowledge of EDCs: It is critical to move beyond the piecemeal, one chemical at a time, one disease at a time, one dose approach currently used by scientists studying animal models, humans or wildlife. Understanding the effects of the mixtures of chemicals to which humans and wildlife are exposed is increasingly important. Assessment of EDC action by scientists needs to take into account the characteristics of the endocrine system that are being disrupted (e.g. low-dose effects and non-monotonic dose–response curves, tissue specificity and windows of exposure across the lifespan). Interdisciplinary efforts that combine knowledge from wildlife, experimental animal and human studies are needed to provide a more holistic approach for identifying the chemicals that are responsible for the increased incidence of endocrine-related disease and dysfunction.

The known EDCs may not be representative of the full range of relevant molecular structures and properties due to a far too narrow focus on halogenated chemicals for many exposure assessments and testing for endocrine disrupting effects. Thus, research is needed to identify other possible EDCs. Endocrine disruption is no longer limited to estrogenic, androgenic and thyroid pathways. Chemicals also interfere with metabolism, fat storage, bone development and the immune system, and this suggests that all endocrine systems can and will be affected by EDCs. Together, these new insights stress a critical need to acquire a better understanding of the endocrine system to determine how EDCs affect normal endocrine function, how windows of exposure may affect disease incidence (particularly for childhood respiratory diseases) and how these effects may be passed on to generations to come.

Furthermore, new approaches are needed to examine the effects of mixtures of endocrine disruptors on disease susceptibility and etiology, as examination of one xvi endocrine disruptor at a time is likely to underestimate the combined risk from simultaneous exposure to multiple endocrine disruptors. Assessment of human health effects due to EDCs needs to include the effects of exposure to chemical mixtures on a single disease as well as the effects of exposure to a single chemical on multiple diseases. Since human studies, while important, cannot show cause and effect, it is critical to develop cause and effect data in animals to support the studies on humans. B. Improved testing for EDCs: Validated screening and testing systems have been developed by a number of governments, and it requires considerable time and effort to ensure that these systems function properly. These systems include both in vitro and in vivo endpoints and various species, including fish, amphibians and mammals. New approaches are also being explored whereby large batteries of high-throughput in vitro tests are being investigated for their ability to predict toxicity, the results of which may be used in hazard identification and potentially risk assessment.

These new approaches are important as one considers the number of chemicals for which there is no information, and these high-throughput assays may provide important, albeit incomplete, information. An additional challenge to moving forward is that EDC research over the past decade has revealed the complex interactions of some chemicals with endocrine systems, which may escape detection in current validated test systems. Finally, it will be important to develop weight-of-evidence approaches that allow effective consideration of research from all levels—from in vitro mechanistic data to human epidemiological data. C. Reducing exposures and thereby vulnerability to disease: It is imperative that we know the nature of EDCs to which humans and wildlife are exposed, together with information about their concentrations in blood, placenta, amniotic fluid and other tissues, across lifespans, sexes, ethnicities (or species of wildlife) and regions.

Many information gaps currently exist with regard to what is found in human and wildlife tissues, more so for developing countries and countries with economies in transition and for chemicals that are less bioaccumulative in the body. Long-term records to help us understand changes in exposures exist only for POPs and only for a few countries. In addition, there is a need to continue expanding the list of chemicals currently examined to include those contained in materials and goods as well as chemical by-products; it is impossible to assess exposure without knowing the chemicals to target. The comprehensive measurement of all exposure events during a lifetime is needed, as opposed to biomonitoring at specific time points, and this requires longitudinal sampling, particularly during critical life stages, such as fetal development, early childhood and the reproductive years.