State of the Science of                                   Endocrine                                   Disrupting          ...
This publication was developed in the IOMC context. The contents do not necessarily reflect the views or stated policies o...
State of the Science of    Endocrine    Disrupting    Chemicals         2012       Summary for Decision-Makers            ...
Contents   Preface								v1. Introduction								12. Key concerns								23. Endocrine systems and endocrine disruption		...
PrefaceThis Summary for Decision-Makers, together with the main           in residues or contaminants in food and other pr...
•	 Roseline Ochieng, Aga Khan University Hospital, Kenya        figures and the layout of the two documents. Nida Besbelli...
1. IntroductionThis document presents summary information                exposure to EDCs, and there is also mountingand k...
2. Key concerns•	 Human and wildlife health depends on the ability to                    ◦	 This lack of data introduces s...
◦	 Developmental neurotoxicity with negative                   •	 Wildlife populations have been affected by endocrine    ...
3. Endocrine systems and endocrine disruption                               For the purposes of this report, we have adopt...
Early prenatal                           Mid-                    Late prenatal                                            ...
systems that are influenced by EDCs that were                                                                          Nuc...
4. Endocrine disruptors and human healthThe data linking exposures to EDCs and human               human disease. Even so,...
5. Why should we be concerned?—Human 	                                                                                    ...
There are other trends of concern in human                                             80                                 ...
6. Endocrine disruptors and wildlife health                               Chemical exposures play a role in the deteriorat...
7. Why should we be concerned?—Population 		       effects in wildlife ♦	 There is a worldwide loss of species or         ...
8. Sensitive periods for endocrine disruptor 		                                                              	            ...
Presentation of Disease over the Lifespan                                         Learning differences/Behaviour          ...
9. Occurrence of and exposures to endocrine 	                                           disruptors                        ...
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
State of the science of endocrine disrupting chemicals   who
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State of the science of endocrine disrupting chemicals who

  1. 1. State of the Science of Endocrine Disrupting Chemicals 2012 Summary for Decision-Makers Edited by Åke Bergman Jerrold J. Heindel Susan Jobling Karen A. Kidd R. Thomas ZoellerINTER-ORGANIZATION PROGRAMME FOR THE SOUND MANAGEMENT OF CHEMICALSA cooperative agreement among FAO, ILO, UNDP, UNEP, UNIDO, UNITAR, WHO, World Bank and OECD
  2. 2. This publication was developed in the IOMC context. The contents do not necessarily reflect the views or stated policies of individual IOMC Participating Organizations. The Inter-Organisation Programme for the Sound Management of Chemicals (IOMC) was established in 1995 following recommendations made by the 1992 UN Conference on Environment and Development to strengthen co-operation and increase international co-ordination in the field of chemical safety. The Participating Organi- sations are FAO, ILO, UNDP, UNEP, UNIDO, UNITAR, WHO, World Bank and OECD. The purpose of the IOMC is to promote co-ordination of the policies and activities pursued by the Participating Organisations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.WHO Library Cataloguing-in-Publication DataState of the science of endocrine disrupting chemicals 2012 / edited by Åke Bergman, Jerrold J. Heindel, Susan Jobling,Karen A. Kidd and R. Thomas Zoeller.1.Endocrine disruptors. 2.Environmental exposure. 3.Animals, Wild. 4.Endocrine system. 5.Hormone Antagonists I.Bergman, Åke. II.Heindel, Jerrold J.III.Jobling, Susan. IV.Kidd, Karen. V.Zoeller, R. Thomas. VI.World Health Organization. VII.United Nations Environment Programme. VIII.Inter-Organization Programme for the Sound Management of Chemicals.© United Nations Environment Programme and the World Health Organization, 2013This Summary Report (UNEP job number: DTI/1554/GE) is based on the main report “State of the Science of EndcorineDisrupting Chemicals - 2012” ISBN: 978-92-807-3274-0 (UNEP) and 978 92 4 150503 1 (WHO) (NLM classification: WK 102).All rights reserved.This publication can be obtained from the United Nations Environment Programme (UNEP) (e-mail: unep.tie@unep.org)or from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264;fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate this publication– whether for sale or for noncommercial distribution – should be addressed to UNEP (e-mail: unep.tie@unep.org) or toWHO Press, at the above address (fax: +41 22 791 4806; e-mail: permissions@who.int).The designations employed and the presentation of the material in this publication do not imply the expression ofany opinion whatsoever on the part of UNEP or WHO concerning the legal status of any country, territory, city orarea or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps repre-sent approximate border lines for which there may not yet be full agreement. The mention of specific companiesor of certain manufacturers’ products does not imply that they are endorsed or recommended by UNEP or WHOin preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names ofproprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by UNEPor WHO to verify the information contained in this publication. However, the published material is being distributedwithout warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of thematerial lies with the reader. In no event shall UNEP or WHO be liable for damages arising from its use. This document is not a formal publication of the UNEP promotes United Nations Environment Programme and the environmentally sound practices World Health Organization and the views expressed globally and in its own activities. This therein are the collective views of the international publication is printed on 100% recycled paper, experts participating in the working group and are using vegetable - based inks and other eco- not necessarily the views of the organizations. friendly practices. Our distribution policy aims to reduce UNEP’s carbon footprint.
  3. 3. State of the Science of Endocrine Disrupting Chemicals 2012 Summary for Decision-Makers An assessment of the state of the science of endocrine disruptors prepared by a group of expertsfor the United Nations Environment Programme and World Health Organization. Edited by Åke Bergman Jerrold J. Heindel Susan Jobling Karen A. Kidd R. Thomas Zoeller
  4. 4. Contents Preface v1. Introduction 12. Key concerns 23. Endocrine systems and endocrine disruption 44. Endocrine disruptors and human health 75. Why should we be concerned?—Human disease trends 86. Endocrine disruptors and wildlife health 107. Why should we be concerned?—Population effects in wildlife 118. Sensitive periods for endocrine disruptor action—Windows of exposure 129. Occurrence of and exposures to endocrine disruptors 1410. The tip of the iceberg 1811. Testing for EDCs 1912. Lessons from the past 2013. Main conclusions and advances in knowledge since 2002 2214. Concluding remarks 2715. References 29 iii
  5. 5. PrefaceThis Summary for Decision-Makers, together with the main in residues or contaminants in food and other products.document, State of the Science of Endocrine Disrupting Therefore, EDCs may be released from the products thatChemicals—2012, presents information and key concerns for contain them.policy-makers on endocrine disruptors as part of the ongoingcollaboration between the World Health Organization (WHO) The protection of the most vulnerable populations fromand the United Nations Environment Programme (UNEP) to environmental threats is a key component of the Millenniumaddress concerns about the potential adverse health effects of Development Goals. As the challenge in meeting the existingchemicals on humans and wildlife. The main messages from goals increases, with work under way in developing countriesthe three chapters of the main document are presented as well. to overcome traditional environmental threats while dealing with poverty, malnutrition and infectious disease, emergingWe live in a world in which man-made chemicals have become issues should be prevented from becoming future traditionala part of everyday life. It is clear that some of these chemical environmental threats. Endocrine disruption is a challenge thatpollutants can affect the endocrine (hormonal) system, and must continue to be addressed in ways that take into accountcertain of these endocrine disruptors may also interfere advances in our knowledge.with the developmental processes of humans and wildlifespecies. Following international recommendations in 1997 UNEP and WHO, in collaboration with a working group ofby the Intergovernmental Forum on Chemical Safety and international experts, are taking a step forward by developingthe Environment Leaders of the Eight regarding the issue of these documents on endocrine disruptors, including scientificendocrine disrupting chemicals (EDCs), WHO, through the information on their impacts on human and wildlife healthInternational Programme on Chemical Safety (IPCS), a joint and key concerns for decision-makers and others concerned.programme of WHO, UNEP and the International Labour The well-being of future human and wildlife generationsOrganization, developed in 2002 a report entitled Global depends on safe environments.Assessment of the State-of-the-Science of Endocrine Disruptors. From late 2010 until mid-2012, the working groupThe Strategic Approach to International Chemicals developed, contributed to and revised sections of the mainManagement (SAICM) was established by the International document during three separate meetings, as well as throughConference on Chemicals Management (ICCM) in February teleconferences. Professor Åke Bergman led the working group2006, with the overall objective to achieve the sound and facilitated the development of this summary with themanagement of chemicals throughout their life cycle so editors in coordination with the working group, UNEP andthat, by 2020, chemicals are used and produced in ways that WHO.minimize significant adverse effects on human health and theenvironment. The following international scientific experts were part of the working group that developed the documents:SAICM recognizes that risk reduction measures need to beimproved to prevent the adverse effects of chemicals on the • Georg Becher, Norwegian Institute of Public Health,health of children, pregnant women, fertile populations, Norwaythe elderly, the poor, workers and other vulnerable groups • Åke Bergman, Stockholm University, Sweden (Leader)and susceptible environments. It states that one measure • Poul Bjerregaard, University of Southern Denmark,to safeguard the health of women and children is the Denmarkminimization of chemical exposures before conception andthrough gestation, infancy, childhood and adolescence. • Riana Bornman, Pretoria Academic Hospital, South Africa • Ingvar Brandt, Uppsala University, SwedenSAICM also specifies that groups of chemicals that might beprioritized for assessment and related studies, such as for the • Jerrold J. Heindel, National Institute of Environmentaldevelopment and use of safe and effective alternatives, include Health Sciences, USAchemicals that adversely affect, inter alia, the reproductive, • Taisen Iguchi, National Institutes of Natural Sciences,endocrine, immune or nervous systems. A resolution to Okazaki, Japaninclude EDCs as an emerging issue under SAICM was adoptedin September 2012 by ICCM at its third session. • Susan Jobling, Brunel University, England • Karen A. Kidd, University of New Brunswick, CanadaEDCs represent a challenge, as their effects depend on boththe level and timing of exposure, being especially critical • Andreas Kortenkamp, University of London and Brunelwhen exposure occurs during development. They have diverse University, Englandapplications, such as pesticides, flame retardants in different • Derek C.G. Muir, Environment Canada, Canadaproducts, plastic additives and cosmetics, which may result v
  6. 6. • Roseline Ochieng, Aga Khan University Hospital, Kenya figures and the layout of the two documents. Nida Besbelli, consultant to the UNEP Secretariat, provided organizational • Niels Erik Skakkebaek, University of Copenhagen, support and assisted with the finalization of references, tables, Denmark and lists of abbreviations and species. A list of chemicals, • Jorma Toppari, University of Turku, Finland including abbreviations/common names and Chemical • Tracey J. Woodruff, University of California at San Abstracts Service registry numbers, was provided by Derek Francisco, USA C.G. Muir and Åke Bergman. A list of species discussed in the summary and main documents was prepared by Nida Besbelli, • R. Thomas Zoeller, University of Massachusetts, USA Åke Bergman, Poul Bjerregaard and Susan Jobling. Further contributions and reviews were received from Heli BathijaThe UNEP/WHO Secretariat for this project included: (WHO), Timothy J. Kasten (UNEP), Desiree Montecillo Narvaez (UNEP), Maria Neira (WHO) and Sheryl Vanderpoel • Marie-Noel Bruné Drisse, Department of Public Health (WHO). and Environment, World Health Organization, Geneva, Switzerland The working group members, scientific experts and • Carlos Dora, Department of Public Health and contributors of text served as individual scientists and not as Environment, World Health Organization, Geneva, representatives of any organization, government or industry. Switzerland All individuals who participated in the preparation of these documents served in their personal capacity and were • Ruth A. Etzel, Department of Public Health and required to sign a Declaration of Interest statement informing Environment, World Health Organization, Geneva, the Responsible Officer if, at any time, there was a conflict Switzerland of interest perceived in their work. Such a procedure was • Agneta Sundén Byléhn, Division of Technology, Industry followed, and no conflicts of interest were identified. and Economics, Chemicals Branch, United Nations Environment Programme, Geneva, Switzerland The development and publication of the two documents were supported by funds provided to UNEP by the Norwegian • Simona Surdu, Department of Public Health and government, the Swedish Environment Ministry, the Swedish Environment, World Health Organization, Geneva, Research Council (FORMAS) and the Swedish Environmental Switzerland Protection Agency. Further support was provided to WHOEditorial assistance was provided by Susan Jobling, and by the United States National Institute of Environmentalreference processing was performed by Ioannis Athanassiadis, Health Sciences (NIEHS) through cooperative agreementÅke Bergman and Hans von Stedingk. Further editorial 1 U01 ES02617. The contents of the documents are solelyassistance was provided by Kathy Prout (WHO) and Marla the responsibility of the contributors and do not necessarilySheffer. John Bellamy assisted with the design of drawings and represent the official views of the NIEHS.vi
  7. 7. 1. IntroductionThis document presents summary information exposure to EDCs, and there is also mountingand key concerns for decision-makers on evidence for effects of these chemicals on thyroidendocrine disrupting chemicals (EDCs) from function, brain function, obesity and metabolism,the full report entitled State of the Science of and insulin and glucose homeostasis.Endocrine Disrupting Chemicals—2012. It is partof the ongoing collaboration between the United The Endocrine Society called for timely actionNations Environment Programme (UNEP) and to prevent harm (Diamanti-Kandarakis et al.,the World Health Organization (WHO) to address 2009), and the European Society for Paediatricconcerns about the potential adverse effects of Endocrinology and the Pediatric Endocrineanthropogenic chemicals. Society, based in the United States of America (USA), put forward a consensus statement callingWe live in a world in which man‐made chemicals for action regarding endocrine disruptors andhave become a part of everyday life. Some of their effects (Skakkebaek et al., 2011).these chemical pollutants can affect the endocrine(hormonal) system and interfere with important In 2012, UNEP and WHO, in collaboration withdevelopmental processes in humans and wildlife. international experts, have taken a step forward by supporting the development of a main documentFollowing international recommendations in 1997 on endocrine disruptors, including scientificby the Intergovernmental Forum on Chemical information on their impacts on human andSafety and the Environment Leaders of the Eight wildlife health, scientific developments over theregarding the issue of EDCs, the International decade since publication of the IPCS (2002) reportProgramme on Chemical Safety (IPCS), a joint and key concerns. The collaboration also includedprogramme of WHO, UNEP and the International the development of the present summary report,Labour Organization, developed in 2002 a report which is aimed at decision-makers and othersentitled Global Assessment of the State‐of‐the‐Science concerned about the future of human and wildlifeof Endocrine Disruptors (Figure 1) (IPCS, 2002). health. The key concerns and main messages from the three chapters of the main document are alsoThe general conclusions from this work were that presented in this summary. although it is clear that certain environmental The main document provides an assessment of the Figure 1. The Global Assess- ment of the State-of-the-Sci- chemicals can interfere with normal hormonal strength of the evidence supporting the hypothesis ence of Endocrine Disruptors processes, there is weak evidence that human that chemicals with endocrine activity are a causal report, as published by health has been adversely affected by exposure factor in the manifestation of specific conditions. IPCS in 2002. to endocrine-active chemicals. However, there is sufficient evidence to conclude that adverse The State of the Science of Endocrine Disrupting endocrine‐mediated effects have occurred in Chemicals—2012 report some wildlife species. Laboratory studies support starts by explaining these conclusions. what endocrine disruption is all aboutThe IPCS (2002) document further concluded and then reviews ourthat there was a need for broad, collaborative and current knowledge ofinternational research initiatives and presented a endocrine disruptinglist of research needs. effects in humans and in wildlife. TheSince 2002, intensive scientific work has improved document ends withour understanding of the impacts of EDCs on a review of sourceshuman and wildlife health. Recent scientific of and exposures toreviews and reports published by the Endocrine EDCs. The presentSociety (Diamanti-Kandarakis et al., 2009), the Summary for Decision-European Commission (Kortenkamp et al., 2011) Makers refers to theand the European Environment Agency (2012) detailed information,illustrate the scientific interest in and complexity of including references,this issue. These documents concluded that there given in the mainis emerging evidence for adverse reproductive report (UNEP/WHO,outcomes (infertility, cancers, malformations) from 2012).Introduction 1
  8. 8. 2. Key concerns• Human and wildlife health depends on the ability to ◦ This lack of data introduces significant uncertainties reproduce and develop normally. This is not possible about the true extent of risks from chemicals that without a healthy endocrine system. potentially could disrupt the endocrine system.• Three strands of evidence fuel concerns over endocrine • Human and wildlife populations all over the world are disruptors: exposed to EDCs. ◦ The high incidence and the increasing trends of many ◦ There is global transport of many known and potential endocrine-related disorders in humans; EDCs through natural processes as well as through commerce, leading to worldwide exposure. ◦ Observations of endocrine-related effects in wildlife populations; ◦ Unlike 10 years ago, we now know that humans and wildlife are exposed to far more EDCs than just those ◦ The identification of chemicals with endocrine that are persistent organic pollutants (POPs). disrupting properties linked to disease outcomes in ◦ Levels of some newer POPs in humans and wildlife laboratory studies. are still increasing, and there is also exposure to less• Many endocrine-related diseases and disorders are on persistent and less bioaccumulative, but ubiquitous, the rise. chemicals. ◦ Large proportions (up to 40%) of young men in some ◦ New sources of human exposure to EDCs and countries have low semen quality, which reduces their potential EDCs, in addition to food and drinking- ability to father children. water, have been identified. ◦ The incidence of genital malformations, such as ◦ Children can have higher exposures to chemicals non-descending testes (cryptorchidisms) and penile compared with adults—for example, through their malformations (hypospadias), in baby boys has hand-to-mouth activity and higher metabolic rate. increased over time or levelled off at unfavourably • The speed with which the increases in disease incidence high rates. have occurred in recent decades rules out genetic ◦ The incidence of adverse pregnancy outcomes, such as factors as the sole plausible explanation. Environmental preterm birth and low birth weight, has increased in and other non-genetic factors, including nutrition, age many countries. of mother, viral diseases and chemical exposures, are ◦ Neurobehavioural disorders associated with thyroid also at play, but are difficult to identify. Despite these disruption affect a high proportion of children in some difficulties, some associations have become apparent: countries and have increased over past decades. ◦ Non-descended testes in young boys are linked ◦ Global rates of endocrine-related cancers (breast, with exposure to diethylstilbestrol (DES) and endometrial, ovarian, prostate, testicular and thyroid) polybrominated diphenyl ethers (PBDEs) and have been increasing over the past 40–50 years. with occupational pesticide exposure during ◦ There is a trend towards earlier onset of breast pregnancy. Recent evidence also shows links with development in young girls in all countries where this the painkiller paracetamol. However, there is little has been studied. This is a risk factor for breast cancer. to suggest that polychlorinated biphenyls (PCBs) ◦ The prevalence of obesity and type 2 diabetes has or dichlorodiphenyldichloroethylene (DDE) dramatically increased worldwide over the last 40 and dichlorodiphenyltrichloroethane (DDT) are years. WHO estimates that 1.5 billion adults worldwide associated with cryptorchidism. are overweight or obese and that the number with type ◦ High exposures to polychlorinated dioxins and 2 diabetes increased from 153 million to 347 million certain PCBs (in women who lack some detoxifying between 1980 and 2008. enzymes) are risk factors in breast cancer. Although• Close to 800 chemicals are known or suspected to exposure to natural and synthetic estrogens is be capable of interfering with hormone receptors, associated with breast cancer, similar evidence linking hormone synthesis or hormone conversion. However, estrogenic environmental chemicals with the disease only a small fraction of these chemicals have been is not available. investigated in tests capable of identifying overt ◦ Prostate cancer risks are related to occupational endocrine effects in intact organisms. exposures to pesticides (of an unidentified nature), to ◦ The vast majority of chemicals in current commercial some PCBs and to arsenic. Cadmium exposure has use have not been tested at all. been linked with prostate cancer in some, but not all, epidemiological studies, although the associations are weak.2 State of the Science of Endocrine Disrupting Chemicals – 2012
  9. 9. ◦ Developmental neurotoxicity with negative • Wildlife populations have been affected by endocrine impacts on brain development is linked with PCBs. disruption, with negative impacts on growth and Attention deficit/hyperactivity disorder (ADHD) reproduction. These effects are widespread and have is overrepresented in populations with elevated been due primarily to POPs. Bans of these chemicals exposure to organophosphate pesticides. Other have reduced exposure and led to recovery of some chemicals have not been investigated. populations. ◦ An excess risk of thyroid cancer was observed among pesticide applicators and their wives, although the ◦ It is therefore plausible that additional EDCs, which have been increasing in the environment and are of nature of the pesticides involved was not defined. recent concern, are contributing to current population • Significant knowledge gaps exist as to associations declines in wildlife species. Wildlife populations that between exposures to EDCs and other endocrine are also challenged by other environmental stressors diseases, as follows: are particularly vulnerable to EDC exposures. ◦ There is very little epidemiological evidence to link • Internationally agreed and validated test methods for EDC exposure with adverse pregnancy outcomes, early the identification of endocrine disruptors capture only onset of breast development, obesity or diabetes. a limited range of the known spectrum of endocrine disrupting effects. This increases the likelihood that ◦ There is almost no information about associations between EDC exposure and endometrial or ovarian harmful effects in humans and wildlife are being cancer. overlooked. ◦ High accidental exposures to PCBs during fetal ◦ For many endocrine disrupting effects, agreed and development or to dioxins in childhood increase the validated test methods do not exist, although scientific risk of reduced semen quality in adulthood. With the tools and laboratory methods are available. exception of these studies, there are no data sets that ◦ For a large range of human health effects, such as female include information about fetal EDC exposures and reproductive disorders and hormonal cancers, there are adult measures of semen quality. no viable laboratory models. This seriously hampers ◦ No studies exist that explore the potential link between progress in understanding the full scale of risks. fetal exposure to EDCs and the risk of testicular cancer occurring 20–40 years later. • Disease risk due to EDCs may be significantly underestimated. • Numerous laboratory studies support the idea that chemical exposures contribute to endocrine disorders ◦ A focus on linking one EDC to one disease severely in humans and wildlife. The most sensitive window of underestimates the disease risk from mixtures of EDCs. We know that humans and wildlife are exposure to EDCs is during critical periods of development, simultaneously exposed to many EDCs; thus, the such as during fetal development and puberty. measurement of the linkage between exposure to ◦ Developmental exposures can cause changes that, mixtures of EDCs and disease or dysfunction is more while not evident as birth defects, can induce physiologically relevant. In addition, it is likely that permanent changes that lead to increased incidence of exposure to a single EDC may cause disease syndromes diseases throughout life. or multiple diseases, an area that has not been adequately studied. ◦ These insights from endocrine disruptor research in animals have an impact on current practice in • An important focus should be on reducing exposures by toxicological testing and screening. Instead of solely a variety of mechanisms. Government actions to reduce studying effects of exposures in adulthood, the exposures, while limited, have proven to be effective effects of exposures during sensitive windows in fetal in specific cases (e.g. bans and restrictions on lead, development, perinatal life, childhood and puberty chlorpyrifos, tributyltin, PCBs and some other POPs). require careful scrutiny. This has contributed to decreases in the frequency of • Worldwide, there has been a failure to adequately disorders in humans and wildlife. address the underlying environmental causes of trends in • Despite substantial advances in our understanding of endocrine diseases and disorders. EDCs, uncertainties and knowledge gaps still exist that ◦ Health-care systems do not have mechanisms in place are too important to ignore. These knowledge gaps to address the contribution of environmental risk hamper progress towards better protection of the public factors to endocrine disorders. The benefits that can and wildlife. An integrated, coordinated international be reaped by adopting primary preventive measures effort is needed to define the role of EDCs in current for dealing with these diseases and disorders have declines in human and wildlife health and in wildlife remained largely unrealized. populations.Key concerns 3
  10. 10. 3. Endocrine systems and endocrine disruption For the purposes of this report, we have adopted differentiation during development and organ the definition of an endocrine disruptor that was formation, as well as most tissue and organ used in the IPCS (2002) document on endocrine functions throughout adulthood (Figure 3). A disruptors (see textbox). Simplified, this means hormone is a molecule produced by an endocrine that endocrine disruptors are chemicals, or gland that travels through the blood to produce chemical mixtures, that interfere with normal effects on distant cells and tissues via integrated hormone action. complex interacting signalling pathways usually involving hormone receptors. There are over To understand endocrine disruption, we must 50 different hormones and hormone-related understand the basic features of the endocrine molecules (cytokines and neurotransmitters) in system, which consists of many interacting humans that integrate and control normal body tissues that talk to each other and the rest of the functions across and between tissues and organs body using signalling mediated by molecules over the lifespan. This is also the case in wildlife.Figure 2. Overview of the called hormones. The human endocrine system Hormones and their signalling pathways areendocrine system. Figure is visualized in Figure 2. It is responsible for critical to the normal functioning of every tissueshows endocrine glands andsome examples of hormo- controlling a large number of processes in the and organ in both vertebrates and invertebratesnes produced. body, including early processes, such as cell and are often quite similar across species.Hypothalamus Pineal GlandProduction of Melatoninantidiuretic hormone (ADH), Definition of EDCsoxytocin and regulatoryhormones (IPCS, 2002)Pituitary Gland Parathyroid GlandsAdenohypophysis (anterior lobe): (on posterior surface of “An endocrine disruptor is anAdrenocorticotropic hormone, thyroid gland) exogenous substance or mixture thatThyroid stimulating hormone, Parathyroid hormoneGrowth hormone, Prolactin, alters function(s) of the endocrineFollicle stimulating hormone, system and consequently causesLuteinizing hormone,Melanocyte stimulating Heart adverse health effects in an intacthormone, Atrial natriuretic peptide organism, or its progeny, or (sub) Neurohypophysis(posterior lobe): populations.”Release of oxytocin Kidneyand ADH Erythropoietin “A potential endocrine disruptor is Calcitriol an exogenous substance or mixtureThyroid Gland ReninThyroxine that possesses properties that mightTriiodothyronine be expected to lead to endocrineCalcitonin disruption in an intact organism, or itsThymus(Undergoes atrophy progeny, or (sub) populations.”during childhood) Gastrointestinal TractThymosins Ghrelin, cholecystokinin, glucagon-like peptide,Adrenal Glands peptide YYEach suprarenal gland issubdivided into: Adipose Tissue Leptin, adiponectin,Suprarenal medulla; others Epinephrine Norepinephrine Pancreatic IsletsSuprarenal cortex: Insulin, glucagon Cortisol, corticosterone, aldosterone, androgens Testis Gonads Testes (male): Androgens (especially testosterone), inhibin Ovaries (female): Estrogens, progestins, inhibin Ovary4 State of the Science of Endocrine Disrupting Chemicals – 2012
  11. 11. Early prenatal Mid- Late prenatal Postnatal Central nervous system (3 weeks - 20 years) Ear (4-20 weeks) Kidneys (4-40 weeks) Heart (3-5 weeks) Limbs (4-8 weeks) Immune system (8-40 weeks: competence and memory birth -10 years) Skeleton (1-12 weeks) Lungs (3-40 weeks: Alveolar phase birth -10 years) Reproductive system (7-40 weeks: maturation in puberty) Week 1-16 Week 17-40 Birth - 25 years Figure 3. Sensitive windows of development. Each tissue has a specific window during development when it is forming. That is the sensitive window for effects of EDCs. Notice that some tissues continue developing after birth and into infancy and childhood, providing a longer window for exposures to affect programming.Table 1. Comparison of hormone and endocrine disruptor action. Hormones Endocrine disruptors Act via hormone receptors Some act via hormone receptors and multiple – Some have multiple receptors receptors – Tissue-specific receptor classes and subtypes – Will cause abnormal receptor function – Hormones normally bind similarly to all receptor – Likely isoform-specific interactions subtypes Active at low doses Some act at low doses, others variable – Blood levels do not always reflect activity – Blood levels do not always reflect activity – May be bound to serum proteins in blood with a – May be bound to serum proteins small percentage free – Effects on hormone blood levels may not reflect – No bioaccumulation on hormone action – Possible bioaccumulation Non-linear dose–response relationships Non-linear dose–response relationships – Always saturable with variable dynamic range – Always saturable with variable dynamic range – Can exhibit non-monotonic dose–response – Can exhibit non-monotonic dose–response relationships relationships – High-dose effects not same as low-dose effects – High-dose effects not same as low-dose effects Tissue-specific and life stage–specific effects Tissue-specific and life stage–specific effects Developmental effects permanent Developmental effects permanent – Programmes brain and endocrine system for – Interferes with programming processes adult function Different end-points vary in sensitivity Different end-points vary in sensitivityEndocrine systems and endocrine disruption 5
  12. 12. systems that are influenced by EDCs that were Nucleus not known just a few years ago. Generally, there Steroid are two pathways by which a chemical could hormone 2 disrupt hormone action: a direct action on a 1 3 hormone–receptor protein complex or a direct Receptor action on a specific protein that controls some protein Hormone- aspect of hormone delivery to the right place at receptor the right time (Figure 3). EDCs exhibit the same complex 4 characteristics as hormones (Table 1), and they can often interfere with all processes controlled by DNA hormones. The affinity of an endocrine disruptor for a hormone receptor is not equivalent to its 5 potency. Chemical potency on a hormone system mRNA is dependent upon many factors. New protein Thus, EDCs act like hormones. Like hormones, which act via binding to receptors (Figure 4) at very low concentrations, EDCs have the ability 6 to be active at low concentrations, many in thePlasma range of current human and wildlife exposures.membrane EDCs can exert effects on more than estrogen,of target cell Cytoplasm androgen and thyroid hormone action. Some are known to interact with multiple hormoneFigure 4. Example of Endocrine disruptors are chemicals that interfere receptors simultaneously. EDCs can work togetherhormone action. Many in some way with hormone action and in so doing to produce additive or synergistic effects not seenhormones act via binding can alter endocrine function such that it leads to with the individual chemicals. EDCs also act onto specific receptors (2) tostimulate the synthesis of adverse effects on human and wildlife health. a variety of physiological processes in a tissue-new proteins (6), which specific manner and sometimes act via dose–then control tissue function. The diverse systems affected by EDCs likely response curves that are non-monotonic (non-Some hormones also act via include all hormonal systems and range from linear). Indeed, as with hormones, it is often notreceptors on the membrane; those controlling the development and function possible to extrapolate low-dose effects from thein that case, the actions are of reproductive organs to the tissues and organs high-dose effects of EDCs. Timing of exposuresmore immediate in nature. regulating metabolism and satiety. Effects on these is also critical, as exposures during development systems can lead to obesity, infertility or reduced likely lead to irreversible effects, whereas the fertility, learning and memory difficulties, adult- effects of adult exposures seem to go away when onset diabetes or cardiovascular disease, as well as the EDC is removed. Sensitivity to endocrine a variety of other diseases. We have only recently disruption is highest during tissue development. understood that EDCs can affect the systems It is important that these specific characteristics of that control fat development and weight gain. EDCs be taken into account when the toxicity of a This is a good example of complex physiological chemical with potential EDC activity is assessed.6 State of the Science of Endocrine Disrupting Chemicals – 2012
  13. 13. 4. Endocrine disruptors and human healthThe data linking exposures to EDCs and human human disease. Even so, it may never be possiblediseases are much stronger now than in 2002. to be absolutely certain that a specific exposureSince human studies can show associations only, causes a specific disease or dysfunction due tonot cause and effect, it is important to use both the complexity of both exposures and diseasehuman and animal data to develop the evidence etiology across the lifespan (Figure 5).for a link between exposures to EDCs and• Reproductive/endocrine • Cardiopulmonary Figure 5. Diseases induced by exposure to EDCs - Breast/prostate cancer - Asthma during development in - Endometriosis - Heart disease/hypertension animal model and human - Infertility - Stroke studies. - Diabetes/metabolic syndrome • Brain/nervous system - Early puberty - Alzheimer disease - Obesity - Parkinson disease• Immune/autoimmune - ADHD/learning disabilities - Susceptibility to infections - Autoimmune diseaseOver the past 10 years, there has been a dramatic 200 Figure 6. Children areshift in focus from investigating associations among the most vulnerable Cancer humans. The figure showsbetween adult exposures to EDCs and disease incidence Cases per Million Children 150 cancer incidence and canceroutcomes to linking developmental exposures mortality among childrento disease outcomes later in life. This is now under 20 years of age in theconsidered the most appropriate approach 100 USA (based on data fromfor most endocrine-related diseases and the United States National Cancer Institute’s Surveil-dysfunctions, based on data presented below Cancer mortality lance, Epidemiology and(section 8). Children are the most vulnerable 50 End Results Program).humans (Figure 6). 0Together, the animal model data and human 1975 1980 1985 1990 1995 2000 2005evidence support the idea that exposure to EDCs Yearsduring fetal development and puberty plays arole in the increased incidences of reproductivediseases, endocrine-related cancers, behaviouraland learning problems, including ADHD,infections, asthma, and perhaps obesity anddiabetes in humans. Exposure to EDCs could impair the health of our children and their children.Endocrine disruptors and human health 7
  14. 14. 5. Why should we be concerned?—Human disease trends ♦ A significant increase in reproductive ♦ An increasing number of chemicals to which problems in some regions of the world over all humans in industrialized areas are exposed the last few decades points to a strong role for have been shown to interfere with hormone unidentified environmental factors in disease synthesis, action or metabolism. etiology. ♦ Experimental animal studies or studies with ♦ Incidences of endocrine cancers, illustrated cells grown in culture have shown that many by country or region in Figures 7 and 8 of these chemicals can also interfere with the for testicular cancer and breast cancer, development and function of mammalian respectively, have also increased during the endocrine systems. same period. In adults, EDC exposures have recently been linked ♦ In certain parts of the world, there has been a with obesity (Figure 9), cardiovascular disease, significant decrease in human fertility rates, diabetes and metabolic syndrome. Many of these which occurred during one generation. There diseases and disorders are increasing in incidence, is also a notable rise in the use of assisted some globally. The global health expenditure on reproductive services. diabetes alone was expected to a total of at least 376 billion USD in 2010 and rise to US$ 490 billion in 2030—reaching 12% of all per capita health-care expenditures (Zhang et al., 2010).Figure 7. Testicular cancer 16 No. of testicular cancer per 100 000 menrates across northern Europe Denmark(from Richiardi et al., 2004; 14used with permission of the 12publisher). Norway 10 Sweden 8 6 Finland 4 Poland Estonia 2 Latvia Lithuania 0 0 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 YearFigure 8. Female breast 160cancer incidence acrossEurope 140 No. of female breast cancer(data from http://data.euro. 120 incidence per 100000who.int/hfadb/). 100 80 60 40 0 1970 1975 1980 1985 1990 1995 2000 2005 2010 2015 Year Austria Finland Latvia Romania Belgium France Lithuania Slovakia Bulgaria Germany Luxembourg Slovenia Cyprus Greece Malta Spain Czech Republic Hungary Netherlands Sweden Denmark Ireland Poland United Kingdom Estonia Italy Portugal European Union8 State of the Science of Endocrine Disrupting Chemicals – 2012
  15. 15. There are other trends of concern in human 80 Figure 9. Past (solid lines)paediatric health. For example, some EDCs and projected (dashed Proportion overweight adults (%) lines) overweight rates incan interact with the thyroid system in animals 70 selected Organisation forand humans. Normal thyroid function is very Economic Co-operation 60important for normal brain development, and Development (OECD)particularly during pregnancy and after birth. 50 countries.EDC exposures have been linked with increasedrates of neurobehavioural disorders, including 40dyslexia, mental retardation, ADHD and autism.In many countries, these types of disorder 30now affect 5–10% of babies born (http://www. 20medscape.org/viewarticle/547415_2); autism 1970 1980 1990 2000 2010 2020spectrum disorders now occur at a rate that Yearapproaches 1% (http://www.cdc.gov/ncbddd/ USA England Canada Spain Austriaautism/addm.html). Italy Australia France Republic of KoreaThe prevalence of paediatric asthma has morethan doubled over the past 20 years and is the contribution of the environment to thesenow the leading cause of child hospitalizations chronic disease trends in humans.and school absenteeism. Certain birth defects,such as those of the male reproductive organs It has been estimated that as much as 24% of(e.g. failure of the testes to descend into the human diseases and disorders are at least in partscrotum), are on the rise. The incidences of due to environmental factors (Prüss-Üstün &paediatric leukaemia and brain cancer have Corvalán, 2006). It is a challenge to identify theserisen, as has the incidence of testicular cancer. factors, but there is also a tremendous opportunityThese are stark health statistics. All of these to improve human health by improving elementscomplex non‐communicable diseases have both of the environment that have an impact on publica genetic and an environmental component, health. The recognition of these challenges andand, since the increases in incidence and opportunities, along with the fact that many of theprevalence cannot be due solely to genetics, most prevalent diseases are associated with theit is important to focus on understanding endocrine system, has led to a focus on EDCs.Why should we be concerned?—Human disease trends 9
  16. 16. 6. Endocrine disruptors and wildlife health Chemical exposures play a role in the deterioration of wildlife health, but understanding the role of EDCs in the global decline of populations or biodiversity is challenging. There are other natural or human‐induced stressors that may confuse the picture. It is also difficult to obtain complete information about all chemicals present in the environment that might contribute to effects on wildlife. The best evidence that EDCs affect wildlife populations comes from long‐term monitoring; for example, numbers of birds and molluscs are clearly increasing in regions where their exposures toFigure 10. (right) Grey seal chemicals (i.e. the pesticide DDT and the antifoulantskull with highly erodedbone tissue associated with tributyltin, respectively) have been reduced.high POP concentrationsduring the 1970s and 1980s Endocrine system function and health have been(photo by Hans Lind, used compromised in wildlife species around the world.with permission). Studies of seals in the heavily polluted Baltic Sea found very high rates of female reproductive species, such as the commercially important oyster, pathologies and reproductive failure in the had collapsed in heavily polluted areas. Reductions 1970s and 1980s, which correlated with PCB in use and exposure have led to a recovery of these contamination. Thanks to declines in PCB pollution, populations. these effects are uncommon today. Disturbances of the normal functioning of the thyroid and of bone There are important parallels between the health have been traced to high POP levels in grey increasing incidence of human disorders and seals (Figure 10). In Dutch and Belgian colonies those observed in wildlife. For example, testicular of common tern, eggs with higher concentrations non‐descent was observed in 68% of males in a of POPs took longer to hatch, and the chicks were population of black-tailed deer in Alaska, USA; smaller in size. Especially in the United Kingdom, similar trends were also observed in Montana, but also in other countries, fish have been widely USA. There is recent evidence that animals living affected by estrogens and anti‐androgens in near humans also have increasing body weight. municipal wastewaters. In male fish, increased levels Moreover, studies of PCB‐exposed wildlife have of the female egg yolk proteins and the occurrence provided important information on exposure of eggs in the testes have been the consequence. levels, early and subclinical effects and the clinical The antifouling agent tributyltin in ship paints has neurotoxicity of these chemicals. The mechanisms disrupted mollusc sexual development worldwide underlying the effects and the outcomes of (Figure 11). By the 1970s, many populations of exposures are often similar to those in humans.Figure 11. Common whelk(Buccinum undatum)showing imposex (i.e. ithas both male and femalegenitalia).10 State of the Science of Endocrine Disrupting Chemicals – 2012
  17. 17. 7. Why should we be concerned?—Population effects in wildlife ♦ There is a worldwide loss of species or 120 Figure 12. Population reduced population numbers of amphibians, declines in wildlife (ver- Population index (= 100 in 1970) tebrates) over 30 years, mammals, birds, reptiles, freshwater and 100 Terrestrial species 1970–2000 (source: World marine fishes (Figure 12) and invertebrates. Wide Fund for Nature Marine species [WWF] and the World ♦ EDCs have been shown to negatively affect 80 Conservation Monitoring body systems that are critical for the health Freshwater species Centre of UNEP, used and survival of wildlife. with permission). 60 The Living Planet Index is an All vertibrate ♦ The current body burdens of POPs such indicator of the state of the world’s biodiversity. It measures trends in species (Living populations of vertebrate species as PCBs, organochlorine pesticides and living in terrestrial, freshwater, and Planet Index) 40 marine ecosystems methylmercury in some fish-eating birds and marine mammal populations are at levels 1970 1975 1980 1985 1990 1995 2000 known to cause effects on breeding and on the Year immune system (Figure 13). Some of these populations are threatened or endangered. a Figure 13. British Colum- 350 ♦ Legal, technical and ethical constraints to Killer whale Harbour seal bia’s (Canada) killer whales 300 (Orcinus orca) and harbour working with wildlife, notably those listed seals (Phoca vitulina) con- PCBs (mg/kg lipid) under endangered species legislation, prevent 250 tain high levels of regulated research to investigate chemical causes of 200 PCBs and moderate levels population declines in these animals. 150 of PBDEs. The figure was prepared using data from ♦ An increasing number of chemicals to which 100 Krahn et al. (2007), Rayne Immunotoxicity wildlife are exposed have been shown to et al. (2004) and Ross et al. 50 interfere with the hormonal and immune (2000, 2012). systems of wildlife species. Most of these 0 chemicals are not monitored in ecosystems. b Exposed wildlife populations are often not Killer whale Harbour seal 1.6 monitored either. PBDEs (µg/kg lipid) ♦ Experimental animal studies have shown 1.2 that many chemicals can interfere with the development and function of endocrine 0.8 systems, leading to effects on behaviour, fecundity, growth, survival and disease 0.4 resistance. This increases the probability that exposure to EDCs could lead to population- 0 level effects in wildlife. ia nd t t nt it ien en ra rg ide ou sid St ns eo es tS tte re Tra fGSubtle effects of EDCs on individual animals may nr ge rn rlo it o er Pu he ha rth ra utresult in devastating effects on wildlife populations nC St No So ee Quover the long term. This is hard to prove until thedeclines in populations are evident, at which pointit may be too late to save these species. those exposed to lower concentrations. As levels of EDCs decline, some wildlife populations haveExposures to EDCs affect the reproductive shown recovery. EDCs have affected immunehealth of wildlife species, but there have been function, resulting in increased susceptibility tofew studies translating these effects to impacts infectious diseases in vertebrates, notably marineat the population level. Notwithstanding this, mammals. Taken together, the evidence shows thathigher rates of reproductive problems are found exposure to endocrine disrupting contaminantsin animals with higher exposure to EDCs than in plays a significant role in wildlife health trends. Wildlife across the globe display EDC-related reproductive effects.Why should we be concerned?—Population effects in wildlife 11
  18. 18. 8. Sensitive periods for endocrine disruptor action—Windows of exposure Hormones and EDCs that alter hormone actions When a tissue is developing, it is more sensitive to can act at all times during life—fetal development, the action of hormones and thus EDCs. infancy, early childhood, puberty, adulthood and old age. The timing of hormone or EDC action The mechanisms by which EDC exposure often determines the strength of their impact. during development can alter the development In the adult, the hormone or EDC has an effect of specific tissues, leading to increased when it is present, but when the hormone or EDC susceptibility to diseases later in life, are is withdrawn, the effect diminishes—much like just beginning to be understood. It is clear insulin levels rising when blood sugar is high and that hormones play an important role in cell then declining when blood sugar declines. differentiation, which leads to the development of tissues and organs. Once tissues and organs In contrast, exposure to hormones or EDCs are fully developed and active, then hormones during development (in utero and infancy and have a different role: to control the integration early childhood in humans) can have permanent of signals between tissues and organ systems effects if the exposure occurs during the period and to maintain normal function. Early when a specific tissue is developing. These effects development (when hormones are controlling may only become visible decades later. This is cell changes to form tissues and organs) is thus called developmental programming. Hormones a very sensitive time frame for EDC action. If control the normal development of tissues from an EDC is present during the developmental the fertilized sperm and egg to the fully developed programming of a tissue, it could disrupt the fetus. Since some tissues continue developing normal hormone levels, leading to changes inFigure 14. The effects ofearly exposures to EDCs after birth—such as the brain and reproductive tissue development—changes that would bemay be manifested any time system—the sensitive period for these tissues stable across the lifetime and possibly conferin life. is extended, sometimes for decades after birth. sensitivity to disease later in life. These effects Developmental Exposures to EDCs Lead to Disease Throughout Life Reproductive Middle Later Gestation Childhood Puberty life life life Exposures to EDCs12 State of the Science of Endocrine Disrupting Chemicals – 2012
  19. 19. Presentation of Disease over the Lifespan Learning differences/Behaviour Asthma Increased sensitivity to infections Atherosclerosis Testicular dysgenesis syndrome Cardiovascular diseaseDevelopmental Exposures Infertility Breast cancer Obesity Prostate cancer Alzheimer disease Altered puberty Fibroids Parkinson disease Premature menopause Age (years) 2 12 25 40 60 70are not likely to be evident at birth, but may animal may affect not only the development Figure 15. Examples ofshow up only later in life, from a few months of her offspring but also their offspring over potential diseases and dysfunctions originatingto decades later (Figures 14 and 15). These several generations. This means that the increase from early exposures todevelopmental effects emphasize that babies in disease rates we are seeing today could in EDCs.and children are not just little adults! part be due to exposures of our grandparents to EDCs, and these effects could increase overSome EDCs produce effects that can cross each generation due to both transgenerationalgenerations (transgenerational effects), such transmission of the altered programming andthat exposure of a pregnant woman or wild continued exposure across generations.Sensitive periods for endocrine disruptor action—Windows of exposure 13
  20. 20. 9. Occurrence of and exposures to endocrine disruptors Since 2002, a large number of chemicals other phytoestrogens, metals, active ingredients in than POPs have been identified as EDCs, and pharmaceuticals, and additives or contaminants these include chemicals that have very different in food, personal care products, cosmetics, properties, sources and fates in the environment plastics, textiles and construction materials. Once compared with POPs. EDCs are both man‐made released into the environment, the more persistent and natural. Some are found in a large variety of chemicals can be carried by air and water currents materials, products, articles and goods. They may to remote locations, and many can be biomagnified also be by-products formed during manufacturing through food webs to high levels in humans and or combustion of wastes. These chemicals are other top predators. Other chemicals have shorter also subjected to biological and environmental lifespans in the environment but are regularlyFigure 16. EDCs find theirway into the environ- transformations that may form other EDCs. released in effluents, in agricultural runoff orment via point and diffuse EDCs are found among many classes of from urban environments, resulting in highsources, as illustrated here. chemicals, including POPs, current-use pesticides, environmental levels near the sources (Figure 16). Sewage system to treatment facillity Emissions to the atmosphere Chemical production Incorporation into consumer products Emissions to the atmosphere Untreated Treated Biosolids wastewater wastewater application Industrial discharges Emissions to rivers, lakes and oceans14 State of the Science of Endocrine Disrupting Chemicals – 2012

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