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    State of the Science of

    EndocrineDisruptingChemicals

    2012Summary for Decision-Makers

    Edited byke BergmanJerrold J. HeindelSusan JoblingKaren A. KiddR. Thomas Zoeller

    INTER-ORGANIZATION PROGRAMME FOR THE SOUND MANAGEMENT OF CHEMICALS

    A cooperative agreement among FAO, ILO, UNDP, UNEP, UNIDO, UNITAR, WHO, World Bank and OECD

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    United Nations Environment Programme and the World Health Organization, 2013

    This 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: [email protected])

    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: [email protected]). Requests for permission to reproduce or translate this publication whether for sale or for noncommercial distribution should be addressed to UNEP (e-mail: [email protected]) or toWHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]).

    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 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 1995following recommendations made by the 1992 UN Conference on Environment and Development to strengthenco-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 isto 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.

    This document is not a formal publication of the

    United Nations Environment Programme and theWorld Health Organization and the views expressedtherein are the collective views of the internationalexperts participating in the working group and arenot necessarily the views of the organizations.

    UNEP promotes

    environmentally sound practices

    globally and in its own activities. This

    publication is printed on 100% recycled paper,

    using vegetable - based inks and other eco-

    friendly practices. Our distribution policy aims to

    reduce UNEPs carbon footprint.

    WHO Library Cataloguing-in-Publication Data

    State of the science of endocrine disrupting chemicals 2012 / edited by ke 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, ke. 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.

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    State of the Science of

    Endocrine

    Disrupting

    Chemicals2012

    Summary for Decision-Makers

    An assessment of the state

    of the science of endocrine disruptors

    prepared by a group of experts

    for the United Nations Environment Programme

    and World Health Organization.

    Edited by

    ke Bergman

    Jerrold J. HeindelSusan Jobling

    Karen A. Kidd

    R. Thomas Zoeller

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    Contents

    Preface v

    1. Introduction 1

    2. Key concerns 2

    3. Endocrine systems and endocrine disruption 4

    4. Endocrine disruptors and human health 7

    5. Why should we be concerned?Human disease trends 8

    6. Endocrine disruptors and wildlife health 10

    7. Why should we be concerned?Population effects in wildlife 11

    8. Sensitive periods for endocrine disruptor actionWindows of exposure 12

    9. Occurrence of and exposures to endocrine disruptors 14

    10. The tip of the iceberg 18

    11. Testing for EDCs 19

    12. Lessons from the past 20

    13. Main conclusions and advances in knowledge since 2002 22

    14. Concluding remarks 27

    15. References 29

    iii

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    Preface

    Tis Summary for Decision-Makers, together with the maindocument, State of the Science of Endocrine DisruptingChemicals2012, presents inormation and key concerns orpolicy-makers on endocrine disruptors as part o the ongoingcollaboration between the World Health Organization (WHO)

    and the United Nations Environment Programme (UNEP) toaddress concerns about the potential adverse health effects ochemicals on humans and wildlie. Te main messages romthe three chapters o the main document are presented as well.

    We live in a world in which man-made chemicals have becomea part o everyday lie. It is clear that some o these chemicalpollutants can affect the endocrine (hormonal) system, andcertain o these endocrine disruptors may also intererewith the developmental processes o humans and wildliespecies. Following international recommendations in 1997by the Intergovernmental Forum on Chemical Saety and

    the Environment Leaders o the Eight regarding the issue oendocrine disrupting chemicals (EDCs), WHO, through theInternational Programme on Chemical Saety (IPCS), a jointprogramme o WHO, UNEP and the International LabourOrganization, developed in 2002 a report entitled GlobalAssessment of the State-of-the-Science of Endocrine Disruptors.

    Te Strategic Approach to International ChemicalsManagement (SAICM) was established by the InternationalConerence on Chemicals Management (ICCM) in February2006, with the overall objective to achieve the sound

    management o chemicals throughout their lie cycle sothat, by 2020, chemicals are used and produced in ways thatminimize significant adverse effects on human health and theenvironment.

    SAICM recognizes that risk reduction measures need to beimproved to prevent the adverse effects o chemicals on thehealth o children, pregnant women, ertile populations,the elderly, the poor, workers and other vulnerable groupsand susceptible environments. It states that one measureto saeguard the health o women and children is theminimization o chemical exposures beore conception and

    through gestation, inancy, childhood and adolescence.

    SAICM also specifies that groups o chemicals that might beprioritized or assessment and related studies, such as or thedevelopment and use o sae and effective alternatives, includechemicals that adversely affect, inter alia, the reproductive,endocrine, immune or nervous systems. A resolution toinclude EDCs as an emerging issue under SAICM was adoptedin September 2012 by ICCM at its third session.

    EDCs represent a challenge, as their effects depend on boththe level and timing o exposure, being especially criticalwhen exposure occurs during development. Tey have diverseapplications, such as pesticides, flame retardants in differentproducts, plastic additives and cosmetics, which may result

    in residues or contaminants in ood and other products.Tereore, EDCs may be released rom the products thatcontain them.

    Te protection o the most vulnerable populations rom

    environmental threats is a key component o the MillenniumDevelopment Goals. As the challenge in meeting the existinggoals increases, with work under way in developing countriesto overcome traditional environmental threats while dealingwith poverty, malnutrition and inectious disease, emergingissues should be prevented rom becoming uture traditionalenvironmental threats. Endocrine disruption is a challenge thatmust continue to be addressed in ways that take into accountadvances in our knowledge.

    UNEP and WHO, in collaboration with a working group ointernational experts, are taking a step orward by developing

    these documents on endocrine disruptors, including scientificinormation on their impacts on human and wildlie healthand key concerns or decision-makers and others concerned.Te well-being o uture human and wildlie generationsdepends on sae environments.

    From late 2010 until mid-2012, the working groupdeveloped, contributed to and revised sections o the maindocument during three separate meetings, as well as throughteleconerences. Proessor ke Bergman led the working groupand acilitated the development o this summary with theeditors in coordination with the working group, UNEP andWHO.

    Te ollowing international scientific experts were part o theworking group that developed the documents:

    Georg Becher, Norwegian Institute of Public Health,Norway

    ke Bergman, Stockholm University, Sweden (Leader)

    Poul Bjerregaard, University of Southern Denmark,Denmark

    Riana Bornman, Pretoria Academic Hospital, South Africa

    Ingvar Brandt, Uppsala University, Sweden

    Jerrold J. Heindel, National Institute of EnvironmentalHealth Sciences, USA

    Taisen Iguchi, National Institutes of Natural Sciences,Okazaki, Japan

    Susan Jobling, Brunel University, England

    Karen A. Kidd, University of New Brunswick, Canada

    Andreas Kortenkamp, University of London and Brunel

    University, England

    Derek C.G. Muir, Environment Canada, Canada

    v

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    Roseline Ochieng, Aga Khan University Hospital, Kenya

    Niels Erik Skakkebaek, University of Copenhagen,Denmark

    Jorma Toppari, University of Turku, Finland

    Tracey J. Woodru, University of California at SanFrancisco, USA

    R. omas Zoeller, University of Massachusetts, USA

    Te UNEP/WHO Secretariat or this project included:

    Marie-Noel Brun Drisse, Department of Public Healthand Environment, World Health Organization, Geneva,Switzerland

    Carlos Dora, Department of Public Health andEnvironment, World Health Organization, Geneva,Switzerland

    Ruth A. Etzel, Department of Public Health and

    Environment, World Health Organization, Geneva,Switzerland

    Agneta Sundn Bylhn, Division of Technology, Industryand Economics, Chemicals Branch, United NationsEnvironment Programme, Geneva, Switzerland

    Simona Surdu, Department of Public Health andEnvironment, World Health Organization, Geneva,Switzerland

    Editorial assistance was provided by Susan Jobling, andreerence processing was perormed by Ioannis Athanassiadis,

    ke Bergman and Hans von Stedingk. Further editorialassistance was provided by Kathy Prout (WHO) and MarlaSheer. John Bellamy assisted with the design of drawings and

    figures and the layout o the two documents. Nida Besbelli,consultant to the UNEP Secretariat, provided organizationalsupport and assisted with the finalization o reerences, tables,and lists o abbreviations and species. A list o chemicals,including abbreviations/common names and ChemicalAbstracts Service registry numbers, was provided by DerekC.G. Muir and ke Bergman. A list o species discussed in thesummary and main documents was prepared by Nida Besbelli,

    ke Bergman, Poul Bjerregaard and Susan Jobling. Furthercontributions and reviews were received rom Heli Bathija(WHO), Timothy J. Kasten (UNEP), Desiree MontecilloNarvaez (UNEP), Maria Neira (WHO) and Sheryl Vanderpoel(WHO).

    Te working group members, scientific experts andcontributors o text served as individual scientists and not asrepresentatives o any organization, government or industry.All individuals who participated in the preparation o thesedocuments served in their personal capacity and were

    required to sign a Declaration o Interest statement inormingthe Responsible Ocer if, at any time, there was a conicto interest perceived in their work. Such a procedure wasollowed, and no conflicts o interest were identified.

    Te development and publication o the two documents weresupported by unds provided to UNEP by the Norwegiangovernment, the Swedish Environment Ministry, the SwedishResearch Council (FORMAS) and the Swedish EnvironmentalProtection Agency. Further support was provided to WHOby the United States National Institute o EnvironmentalHealth Sciences (NIEHS) through cooperative agreement

    1 U01 ES02617. Te contents o the documents are solelythe responsibility o the contributors and do not necessarilyrepresent the ocial views of the NIEHS.

    vi

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    1

    1. IntroductionTis document presents summary inormationand key concerns or decision-makers onendocrine disrupting chemicals (EDCs) romthe ull report entitled State of the Science ofEndocrine Disrupting Chemicals2012. It is part

    o the ongoing collaboration between the UnitedNations Environment Programme (UNEP) andthe World Health Organization (WHO) to addressconcerns about the potential adverse effects oanthropogenic chemicals.

    We live in a world in which manmade chemicalshave become a part o everyday lie. Some othese chemical pollutants can affect the endocrine(hormonal) system and interere with importantdevelopmental processes in humans and wildlie.

    Following international recommendations in 1997by the Intergovernmental Forum on ChemicalSaety and the Environment Leaders o the Eightregarding the issue o EDCs, the InternationalProgramme on Chemical Saety (IPCS), a jointprogramme o WHO, UNEP and the InternationalLabour Organization, developed in 2002 a reportentitled Global Assessment of the StateoftheScienceof Endocrine Disruptors(Figure 1) (IPCS, 2002).

    Te general conclusions rom this work were that

    although it is clear that certain environmental

    chemicals can interfere with normal hormonal

    processes, there is weak evidence that human

    health has been adversely affected by exposure

    to endocrine-active chemicals. However, there

    is sufficient evidence to conclude that adverse

    endocrinemediated effects have occurred in

    some wildlife species. Laboratory studies support

    these conclusions.

    Te IPCS (2002) document urther concluded

    that there was a need or broad, collaborative andinternational research initiatives and presented alist o research needs.

    Since 2002, intensive scientific work has improvedour understanding o the impacts o EDCs onhuman and wildlife health. Recent scienticreviews and reports published by the EndocrineSociety (Diamanti-Kandarakis et al., 2009), theEuropean Commission (Kortenkamp et al., 2011)and the European Environment Agency (2012)

    illustrate the scientific interest in and complexity othis issue. Tese documents concluded that thereis emerging evidence or adverse reproductiveoutcomes (inertility, cancers, malormations) rom

    Figure 1.Te Global Assess-ment of the State-of-the-Sci-

    ence of Endocrine Disruptorsreport, as published byIPCS in 2002.

    exposure to EDCs, and there is also mountingevidence or effects o these chemicals on thyroidunction, brain unction, obesity and metabolism,and insulin and glucose homeostasis.

    Te Endocrine Society called or timely actionto prevent harm (Diamanti-Kandarakis et al.,2009), and the European Society or PaediatricEndocrinology and the Pediatric EndocrineSociety, based in the United States o America(USA), put orward a consensus statement callingor action regarding endocrine disruptors andtheir effects (Skakkebaek et al., 2011).

    In 2012, UNEP and WHO, in collaboration withinternational experts, have taken a step orward bysupporting the development o a main document

    on endocrine disruptors, including scientificinormation on their impacts on human andwildlie health, scientific developments over thedecade since publication o the IPCS (2002) reportand key concerns. Te collaboration also includedthe development o the present summary report,which is aimed at decision-makers and othersconcerned about the uture o human and wildliehealth. Te key concerns and main messages romthe three chapters o the main document are alsopresented in this summary.

    Te main document provides an assessment o thestrength o the evidence supporting the hypothesisthat chemicals with endocrine activity are a causalactor in the maniestation o specific conditions.

    Te State of the Science of Endocrine DisruptingChemicals2012reportstarts by explainingwhat endocrinedisruption is all aboutand then reviews our

    current knowledge oendocrine disruptingeffects in humansand in wildlie. Tedocument ends witha review o sourceso and exposures toEDCs. Te presentSummary for Decision-

    Makersreers to thedetailed inormation,including reerences,given in the mainreport (UNEP/WHO,2012).

    I 1

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    2 S S E D C

    2. Key concerns Human and wildlife health depends on the ability to

    reproduce and develop normally. Tis is not possible

    without a healthy endocrine system.

    Tree strands of evidence fuel concerns over endocrine

    disruptors:

    Te high incidence and the increasing trends o manyendocrine-related disorders in humans;

    Observations o endocrine-related effects in wildliepopulations;

    Te identification o chemicals with endocrinedisrupting properties linked to disease outcomes inlaboratory studies.

    Many endocrine-related diseases and disorders are on

    the rise.

    Large proportions (up to 40%) o young men in somecountries have low semen quality, which reduces theirability to ather children.

    Te incidence o genital malormations, such asnon-descending testes (cryptorchidisms) and penilemalormations (hypospadias), in baby boys hasincreased over time or levelled off at unavourablyhigh rates.

    Te incidence o adverse pregnancy outcomes, such aspreterm birth and low birth weight, has increased inmany countries.

    Neurobehavioural disorders associated with thyroiddisruption affect a high proportion o children in somecountries and have increased over past decades.

    Global rates o endocrine-related cancers (breast,endometrial, ovarian, prostate, testicular and thyroid)have been increasing over the past 4050 years.

    Tere is a trend towards earlier onset o breastdevelopment in young girls in all countries where thishas been studied. Tis is a risk actor or breast cancer.

    Te prevalence o obesity and type 2 diabetes hasdramatically increased worldwide over the last 40

    years. WHO estimates that 1.5 billion adults worldwideare overweight or obese and that the number with type2 diabetes increased rom 153 million to 347 millionbetween 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 eects in intact organisms.

    Te vast majority o chemicals in current commercialuse have not been tested at all.

    Tis lack o data introduces significant uncertaintiesabout the true extent o risks rom chemicals thatpotentially could disrupt the endocrine system.

    Human and wildlife populations all over the world are

    exposed to EDCs.

    Tere is global transport o many known and potentialEDCs through natural processes as well as throughcommerce, leading to worldwide exposure.

    Unlike 10 years ago, we now know that humans andwildlie are exposed to ar more EDCs than just thosethat are persistent organic pollutants (POPs).

    Levels o some newer POPs in humans and wildlieare still increasing, and there is also exposure to lesspersistent and less bioaccumulative, but ubiquitous,chemicals.

    New sources o human exposure to EDCs andpotential EDCs, in addition to ood and drinking-water, have been identified.

    Children can have higher exposures to chemicalscompared with adultsor example, through theirhand-to-mouth activity and higher metabolic rate.

    Te speed with which the increases in disease incidence

    have occurred in recent decades rules out genetic

    factors as the sole plausible explanation. Environmental

    and other non-genetic factors, including nutrition, age

    of mother, viral diseases and chemical exposures, are

    also at play, but are dicult to identify. Despite thesediculties, some associations have become apparent:

    Non-descended testes in young boys are linkedwith exposure to diethylstilbestrol (DES) andpolybrominated diphenyl ethers (PBDEs) andwith occupational pesticide exposure duringpregnancy. Recent evidence also shows links withthe painkiller paracetamol. However, there is littleto suggest that polychlorinated biphenyls (PCBs)or dichlorodiphenyldichloroethylene (DDE)and dichlorodiphenyltrichloroethane (DDT) are

    associated with cryptorchidism.

    High exposures to polychlorinated dioxins andcertain PCBs (in women who lack some detoxiyingenzymes) are risk actors in breast cancer. Althoughexposure to natural and synthetic estrogens isassociated with breast cancer, similar evidence linkingestrogenic environmental chemicals with the diseaseis not available.

    Prostate cancer risks are related to occupationalexposures to pesticides (o an unidentified nature), to

    some PCBs and to arsenic. Cadmium exposure hasbeen linked with prostate cancer in some, but not all,epidemiological studies, although the associations areweak.

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    3

    Developmental neurotoxicity with negativeimpacts on brain development is linked with PCBs.Attention deficit/hyperactivity disorder (ADHD)is overrepresented in populations with elevatedexposure to organophosphate pesticides. Otherchemicals have not been investigated.

    An excess risk o thyroid cancer was observed amongpesticide applicators and their wives, although thenature o the pesticides involved was not defined.

    Signicant knowledge gaps exist as to associations

    between exposures to EDCs and other endocrine

    diseases, as follows:

    Tere is very little epidemiological evidence to linkEDC exposure with adverse pregnancy outcomes, earlyonset o breast development, obesity or diabetes.

    Tere is almost no inormation about associationsbetween EDC exposure and endometrial or ovariancancer.

    High accidental exposures to PCBs during etaldevelopment or to dioxins in childhood increase therisk o reduced semen quality in adulthood. With theexception o these studies, there are no data sets thatinclude inormation about etal EDC exposures andadult measures o semen quality.

    No studies exist that explore the potential link betweenetal exposure to EDCs and the risk o testicular canceroccurring 2040 years later.

    Numerous laboratory studies support the idea that

    chemical exposures contribute to endocrine disorders

    in humans and wildlife. Te most sensitive window of

    exposure to EDCs is during critical periods of development,

    such as during fetal development and puberty.

    Developmental exposures can cause changes that,while not evident as birth deects, can inducepermanent changes that lead to increased incidence odiseases throughout lie.

    Tese insights rom endocrine disruptor research

    in animals have an impact on current practice intoxicological testing and screening. Instead o solelystudying effects o exposures in adulthood, theeffects o exposures during sensitive windows in etaldevelopment, perinatal lie, childhood and pubertyrequire careul 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 placeto address the contribution o environmental risk

    actors to endocrine disorders. Te benefits that canbe reaped by adopting primary preventive measuresor dealing with these diseases and disorders haveremained largely unrealized.

    Wildlife populations have been aected by endocrine

    disruption, with negative impacts on growth and

    reproduction. Tese eects 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 thereore plausible that additional EDCs, whichhave been increasing in the environment and are orecent concern, are contributing to current populationdeclines in wildlie species. Wildlie populations thatare also challenged by other environmental stressorsare particularly vulnerable to EDC exposures.

    Internationally agreed and validated test methods for

    the identication of endocrine disruptors capture only

    a limited range of the known spectrum of endocrine

    disrupting eects. Tis increases the likelihood that

    harmful eects in humans and wildlife are beingoverlooked.

    For many endocrine disrupting effects, agreed andvalidated test methods do not exist, although scientifictools and laboratory methods are available.

    For a large range o human health effects, such as emalereproductive disorders and hormonal cancers, there areno viable laboratory models. Tis seriously hampersprogress in understanding the ull scale o risks.

    Disease risk due to EDCs may be signicantly

    underestimated.

    A ocus on linking one EDC to one disease severelyunderestimates the disease risk rom mixtureso EDCs. We know that humans and wildlie aresimultaneously exposed to many EDCs; thus, themeasurement o the linkage between exposure tomixtures o EDCs and disease or dysunction is morephysiologically relevant. In addition, it is likely thatexposure to a single EDC may cause disease syndromesor multiple diseases, an area that has not beenadequately studied.

    An important focus should be on reducing exposures bya variety of mechanisms. Government actions to reduce

    exposures, while limited, have proven to be eective

    in specic cases (e.g. bans and restrictions on lead,

    chlorpyrifos, tributyltin, PCBs and some other POPs).

    Tis 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. Tese knowledge gaps

    hamper progress towards better protection of the public

    and wildlife. An integrated, coordinated internationaleort is needed to dene the role of EDCs in current

    declines in human and wildlife health and in wildlife

    populations.

    K

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    4 S S E D C

    3. Endocrine systems and endocrine disruption

    Definition of EDCs

    (IPCS, )

    An endocrine disruptoris 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.

    Apotential endocrine disruptoris

    an exogenous substance or mixture

    that possesses properties that might

    be expected to lead to endocrine

    disruption in an intact organism, or its

    progeny, or (sub) populations.

    Figure 2.Overview o theendocrine system. Figureshows endocrine glands andsome examples o hormo-nes produced.

    For the purposes o this report, we have adoptedthe definition o an endocrine disruptor that wasused in the IPCS (2002) document on endocrinedisruptors (see textbox). Simplified, this meansthat endocrine disruptors are chemicals, or

    chemical mixtures, that interere with normalhormone action.

    To understand endocrine disruption, we mustunderstand the basic eatures o the endocrinesystem, which consists o many interactingtissues that talk to each other and the rest o thebody using signalling mediated by moleculescalled hormones. Te human endocrine systemis visualized in Figure 2. It is responsible orcontrolling a large number o processes in thebody, including early processes, such as cell

    differentiation during development and organormation, as well as most tissue and organunctions throughout adulthood (Figure 3). Ahormone is a molecule produced by an endocrinegland that travels through the blood to produce

    effects on distant cells and tissues via integratedcomplex interacting signalling pathways usuallyinvolving hormone receptors. Tere are over50 different hormones and hormone-relatedmolecules (cytokines and neurotransmitters) inhumans that integrate and control normal bodyunctions across and between tissues and organsover the liespan. Tis is also the case in wildlie.Hormones and their signalling pathways arecritical to the normal unctioning o every tissueand organ in both vertebrates and invertebratesand are ofen quite similar across species.

    Hypothalamus

    Production of

    antidiuretic hormone (ADH),

    oxytocin and regulatory

    hormones

    Pituitary Gland

    Adenohypophysis (anterior lobe):Adrenocorticotropic hormone,

    Thyroid s tim ulating horm one,

    Growth hormone, Prolactin,

    Follicle stimulating hormone,Luteinizing hormone,

    Melanocyte stimulating

    hormone,

    Neurohypophysis

    (posterior lobe):Release of oxytocin

    and ADH

    Thyroid Gland

    Thyrox ine

    Trii odothy ron ine

    Calcitonin

    Thymus

    (Undergoes atrophy

    during childhood)

    Thymos ins

    Adrenal GlandsEach suprarenal gland is

    subdivided into:

    Suprarenal medulla;Epinephrine

    Norepinephrine

    Suprarenal cortex:

    Cortisol, corticosterone,aldosterone, androgens

    Parathyroid Glands

    (on posterior surface of

    thyroid gland)

    Parathyroid hormone

    Heart

    Atrial natriureticpeptide

    Kidney

    ErythropoietinCalcitriol

    Renin

    Gastrointestinal Tract

    Ghrelin, cholecystokinin,

    glucagon-like peptide,

    peptide YY

    Pancreatic Islets

    Insulin, glucagon

    Gonads

    Testes (ma le) :Androgens (especially

    testosterone), inhibin

    Ovaries (female):Estrogens, progestins,

    inhibin

    Ovary

    Testis

    Pineal Gland

    Melatonin

    Adipose Tissue

    Leptin, adiponectin,others

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    5

    Week 1-16 Week 17-40 Birth - 25 years

    Early prenatal Mid- Late prenatal Postnatal

    Central nervous system (3 weeks - 20 years)

    Ear (4-20 weeks)

    Heart (3-5 weeks)

    Limbs (4-8 weeks)

    Skeleton (1-12 weeks)

    Kidneys (4-40 weeks)

    Reproductive system (7-40 weeks: maturation in puberty)

    Immune system (8-40 weeks: competence and memory birth -1 0 years)

    Lungs (3-40 weeks: Alveolar phase birth -10 years)

    Figure 3.Sensitive windows o development. Each tissue has aspecific window during development when it is orming. Tat isthe sensitive window or effects o EDCs. Notice that some tissuescontinue developing afer birth and into inancy and childhood,providing a longer window or exposures to affect programming.

    Hormones Endocrine disruptors

    Act via hormone receptors

    Some have multiple receptors

    Tissue-specific receptor classes and subtypes

    Hormones normally bind similarly to all receptorsubtypes

    Some act via hormone receptors and multiplereceptors

    Will cause abnormal receptor function

    Likely isoform-specific interactions

    Active at low doses

    Blood levels do not always reflect activity

    May be bound to serum proteins in blood with a

    small percentage free No bioaccumulation

    Some act at low doses, others variable

    Blood levels do not always reflect activity

    May be bound to serum proteins

    Effects on hormone blood levels may not reflecton hormone action

    Possible bioaccumulation

    Non-linear doseresponse relationships

    Always saturable with variable dynamic range

    Can exhibit non-monotonic doseresponserelationships

    High-dose effects not same as low-dose effects

    Non-linear doseresponse relationships

    Always saturable with variable dynamic range

    Can exhibit non-monotonic doseresponserelationships

    High-dose effects not same as low-dose effects

    Tissue-specific and life stagespecific effects Tissue-specific and life stagespecific effects

    Developmental effects permanent

    Programmes brain and endocrine system foradult function

    Developmental effects permanent

    Interferes with programming processes

    Different end-points vary in sensitivity Different end-points vary in sensitivity

    able 1.Comparison o hormone and endocrine disruptor action.

    E

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    6 S S E D C

    Figure 4.Example ohormone action. Manyhormones act via bindingto specific receptors (2) tostimulate the synthesis onew proteins (6), whichthen control tissue unction.Some hormones also act viareceptors on the membrane;

    in that case, the actions aremore immediate in nature.

    Endocrine disruptors are chemicals that intererein some way with hormone action and in so doingcan alter endocrine unction such that it leads toadverse effects on human and wildlie health.

    Te diverse systems affected by EDCs likelyinclude all hormonal systems and range romthose controlling the development and unction

    o reproductive organs to the tissues and organsregulating metabolism and satiety. Effects on thesesystems can lead to obesity, inertility or reducedfertility, learning and memory diculties, adult-onset diabetes or cardiovascular disease, as well asa variety o other diseases. We have only recentlyunderstood that EDCs can affect the systemsthat control at development and weight gain.Tis is a good example o complex physiological

    systems that are influenced by EDCs that werenot known just a ew years ago. Generally, thereare two pathways by which a chemical coulddisrupt hormone action: a direct action on ahormonereceptor protein complex or a directaction on a specific protein that controls someaspect o hormone delivery to the right place atthe right time (Figure 3). EDCs exhibit the same

    characteristics as hormones (able 1), and theycan ofen interere with all processes controlled byhormones. e anity of an endocrine disruptoror a hormone receptor is not equivalent to itspotency. Chemical potency on a hormone systemis dependent upon many actors.

    Tus, EDCs act like hormones. Like hormones,which act via binding to receptors (Figure 4) atvery low concentrations, EDCs have the abilityto be active at low concentrations, many in the

    range o current human and wildlie exposures.EDCs can exert effects on more than estrogen,androgen and thyroid hormone action. Someare known to interact with multiple hormonereceptors simultaneously. EDCs can work togetherto produce additive or synergistic effects not seenwith the individual chemicals. EDCs also act ona variety o physiological processes in a tissue-specific manner and sometimes act via doseresponse curves that are non-monotonic (non-linear). Indeed, as with hormones, it is ofen notpossible to extrapolate low-dose effects rom the

    high-dose eects of EDCs. Timing of exposuresis also critical, as exposures during developmentlikely lead to irreversible effects, whereas theeffects o adult exposures seem to go away whenthe EDC is removed. Sensitivity to endocrinedisruption is highest during tissue development.It is important that these specific characteristics oEDCs be taken into account when the toxicity o achemical with potential EDC activity is assessed.

    1

    2

    3

    4

    5

    6

    Steroid

    hormone

    Hormone-

    receptor

    complex

    Receptor

    protein

    New

    protein

    Nucleus

    DNA

    mRNA

    Plasmamembrane

    of target cell Cytoplasm

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    7

    4. Endocrine disruptors and human health

    Figure 5.Diseases inducedby exposure to EDCsduring development inanimal model and humanstudies.

    Figure 6.Children areamong the most vulnerablehumans. Te figure showscancer incidence and cancermortality among childrenunder 20 years o age in theUSA (based on data romthe United States NationalCancer Institutes Surveil-

    lance, Epidemiology andEnd Results Program).

    EXPOSURETOEDCSCOULDIMPAIRTHEHEALTHOFOURCHILDRENAND

    THEIRCHILDREN.

    Te data linking exposures to EDCs and humandiseases are much stronger now than in 2002.Since human studies can show associations only,not cause and effect, it is important to use bothhuman and animal data to develop the evidence

    or a link between exposures to EDCs and

    human disease. Even so, it may never be possibleto be absolutely certain that a specific exposurecauses a specific disease or dysunction due tothe complexity o both exposures and diseaseetiology across the liespan (Figure 5).

    E

    Reproductive/endocrine

    - Breast/prostate cancer

    - Endometriosis

    - Infertility

    - Diabetes/metabolic syndrome

    - Early puberty

    - Obesity

    Immune/autoimmune

    - Susceptibility to infections

    - Autoimmune disease

    Cardiopulmonary

    - Asthma

    - Heart disease/hypertension

    - Stroke

    Brain/nervous system

    - Alzheimer disease

    - Parkinson disease

    - ADHD/learning disabilities

    Over the past 10 years, there has been a dramaticshif in ocus rom investigating associationsbetween adult exposures to EDCs and diseaseoutcomes to linking developmental exposuresto disease outcomes later in lie. Tis is nowconsidered the most appropriate approachor most endocrine-related diseases and

    dysunctions, based on data presented below(section 8). Children are the most vulnerablehumans (Figure 6).

    Together, the animal model data and humanevidence support the idea that exposure to EDCsduring etal development and puberty plays arole in the increased incidences o reproductivediseases, endocrine-related cancers, behaviouraland learning problems, including ADHD,inections, asthma, and perhaps obesity anddiabetes in humans.

    200

    150

    100

    Cases

    perMillionChildren

    50

    19800

    1975 19901985 20001995 2005

    Years

    Cancerincidence

    Cancermortality

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    8 S S E D C

    Figure 8.Female breastcancer incidence acrossEurope

    (data rom http://data.euro.who.int/hadb/).

    Figure 7.Testicular cancerrates across northern Europe(from Richiardi et al., 2004;used with permission o thepublisher).

    A significant increase in reproductiveproblems in some regions o the world overthe last ew decades points to a strong role orunidentified environmental actors in diseaseetiology.

    Incidences o endocrine cancers, illustratedby country or region in Figures 7 and 8or testicular cancer and breast cancer,respectively, have also increased during thesame period.

    In certain parts o the world, there has been asignificant decrease in human ertility rates,which occurred during one generation. Tereis also a notable rise in the use o assisted

    reproductive services.

    An increasing number o chemicals to whichall humans in industrialized areas are exposedhave been shown to interere with hormonesynthesis, action or metabolism.

    Experimental animal studies or studies withcells grown in culture have shown that manyo these chemicals can also interere with thedevelopment and unction o mammalianendocrine systems.

    In adults, EDC exposures have recently been linkedwith obesity (Figure 9), cardiovascular disease,diabetes and metabolic syndrome. Many o thesediseases and disorders are increasing in incidence,some globally. Te global health expenditure on

    diabetes alone was expected to a total o at least 376billion USD in 2010 and rise to US$ 490 billion in2030reaching 12% o all per capita health-careexpenditures (Zhang et al., 2010).

    20001945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995

    14

    16

    12

    10

    8

    6

    4

    2

    00

    No.oftesticularcan

    cerper100000men

    Denmark

    Norway

    Sweden

    Finland

    Poland

    Estonia

    Latvia Lithuania

    Year

    160

    140

    120

    100

    20152000 20102005

    80

    60

    40

    01 97 0 1 97 5 1 98 0 1 99 0 1 99 51985

    AustriaBelgiumBulgariaCyprusCzech RepublicDenmarkEstonia

    FinlandLithuania

    Malta

    Slovakia

    Slovenia

    Sweden

    Germany

    France

    GreeceHungaryIrelandItaly

    Latvia

    Luxembourg

    NetherlandsPolandPortugal

    Romania

    Spain

    United KingdomEuropean Union

    No.offemalebreastcancer

    incidenceper100000

    Year

    5. Why should we be concerned?Humandisease trends

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    9

    Figure 9.Past (solid lines)and projected (dashedlines) overweight rates inselected Organisation orEconomic Co-operationand Development (OECD)countries.

    Tere are other trends o concern in humanpaediatric health. For example, some EDCscan interact with the thyroid system in animalsand humans. Normal thyroid unction is veryimportant or normal brain development,particularly during pregnancy and afer birth.EDC exposures have been linked with increasedrates o neurobehavioural disorders, including

    dyslexia, mental retardation, ADHD and autism.In many countries, these types o disordernow affect 510% o babies born (http://www.medscape.org/viewarticle/547415_2); autismspectrum disorders now occur at a rate thatapproaches 1% (http://www.cdc.gov/ncbddd/autism/addm.html).

    Te prevalence o paediatric asthma has morethan doubled over the past 20 years and isnow the leading cause o child hospitalizations

    and school absenteeism. Certain birth deects,such as those o the male reproductive organs(e.g. ailure o the testes to descend into thescrotum), are on the rise. Te incidences opaediatric leukaemia and brain cancer haverisen, as has the incidence o testicular cancer.Tese are stark health statistics. All o thesecomplex noncommunicable diseases have botha genetic and an environmental component,and, since the increases in incidence andprevalence cannot be due solely to genetics,it is important to ocus on understanding

    W H

    80

    Propor

    tionoverweightadults(%)

    Year

    70

    60

    50

    40

    30

    201970 1980 1990 2000 2010 2020

    USA England Canada Spain Austria

    I taly Australia France Repu blic of Ko rea

    the contribution o the environment to thesechronic disease trends in humans.

    It has been estimated that as much as 24% ohuman diseases and disorders are at least in partdue to environmental actors (Prss-stn &Corvaln, 2006). It is a challenge to identiy theseactors, but there is also a tremendous opportunityto improve human health by improving elementso the environment that have an impact on publichealth. Te recognition o these challenges andopportunities, along with the act that many o themost prevalent diseases are associated with theendocrine system, has led to a ocus on EDCs.

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    10 S S E D C

    6. Endocrine disruptors and wildlife health

    Figure 11.Common whelk(Buccinum undatum)

    showing imposex (i.e. ithas both male and emalegenitalia).

    Figure 10.(right) Grey sealskull with highly erodedbone tissue associated withhigh POP concentrationsduring the 1970s and 1980s(photo by Hans Lind, used

    with permission).

    Chemical exposures play a role in the deteriorationo wildlie health, but understanding the roleo EDCs in the global decline o populations orbiodiversity is challenging. Tere are other naturalor humaninduced stressors that may conuse

    the picture. It is also dicult to obtain completeinormation about all chemicals present in theenvironment that might contribute to effects onwildlie. Te best evidence that EDCs affect wildliepopulations comes rom longterm monitoring; orexample, numbers o birds and molluscs are clearlyincreasing in regions where their exposures tochemicals (i.e. the pesticide DDT and the antifoulanttributyltin, respectively) have been reduced.

    Endocrine system unction and health have beencompromised in wildlie species around the world.

    Studies o seals in the heavily polluted Baltic Seaound very high rates o emale reproductivepathologies and reproductive ailure in the1970s and 1980s, which correlated with PCBcontamination. Tanks to declines in PCB pollution,these effects are uncommon today. Disturbances othe normal unctioning o the thyroid and o bonehealth have been traced to high POP levels in greyseals (Figure 10). In Dutch and Belgian colonieso common tern, eggs with higher concentrationso POPs took longer to hatch, and the chicks were

    smaller in size. Especially in the United Kingdom,but also in other countries, fish have been widelyaffected by estrogens and antiandrogens inmunicipal wastewaters. In male fish, increased levelso the emale egg yolk proteins and the occurrenceo eggs in the testes have been the consequence.Te antiouling agent tributyltin in ship paints hasdisrupted mollusc sexual development worldwide(Figure 11). By the 1970s, many populations o

    species, such as the commercially important oyster,had collapsed in heavily polluted areas. Reductionsin use and exposure have led to a recovery o thesepopulations.

    Tere are important parallels between theincreasing incidence o human disorders andthose observed in wildlie. For example, testicularnondescent was observed in 68% o males in apopulation o black-tailed deer in Alaska, USA;similar trends were also observed in Montana,USA. Tere is recent evidence that animals livingnear humans also have increasing body weight.Moreover, studies o PCBexposed wildlie haveprovided important inormation on exposurelevels, early and subclinical effects and the clinicalneurotoxicity o these chemicals. Te mechanismsunderlying the effects and the outcomes oexposures are ofen similar to those in humans.

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    11

    Tere is a worldwide loss o species orreduced population numbers o amphibians,mammals, birds, reptiles, reshwater andmarine fishes (Figure 12) and invertebrates.

    EDCs have been shown to negatively affectbody systems that are critical or the healthand survival o wildlie.

    Te current body burdens o POPs suchas PCBs, organochlorine pesticides andmethylmercury in some fish-eating birds andmarine mammal populations are at levelsknown to cause effects on breeding and on theimmune system (Figure 13). Some o thesepopulations are threatened or endangered.

    Legal, technical and ethical constraints toworking with wildlie, notably those listedunder endangered species legislation, preventresearch to investigate chemical causes opopulation declines in these animals.

    An increasing number o chemicals to whichwildlie are exposed have been shown tointerere with the hormonal and immunesystems o wildlie species. Most o thesechemicals are not monitored in ecosystems.Exposed wildlie populations are ofen not

    monitored either. Experimental animal studies have shown

    that many chemicals can interere with thedevelopment and unction o endocrinesystems, leading to effects on behaviour,ecundity, growth, survival and diseaseresistance. Tis increases the probability thatexposure to EDCs could lead to population-level effects in wildlie.

    Subtle effects o EDCs on individual animals mayresult in devastating effects on wildlie populationsover the long term. Tis is hard to prove until thedeclines in populations are evident, at which pointit may be too late to save these species.

    Exposures to EDCs affect the reproductivehealth o wildlie species, but there have beenew studies translating these effects to impactsat the population level. Notwithstanding this,higher rates o reproductive problems are oundin animals with higher exposure to EDCs than in

    Figure 12.Populationdeclines in wildlie (ver-tebrates) over 30 years,19702000 (source: WorldWide Fund or Nature[WWF] and the WorldConservation MonitoringCentre o UNEP, usedwith permission).

    7. Why should we be concerned?Populationeffects in wildlife

    Figure 13.British Colum-

    bias (Canada) killer whales(Orcinus orca) and harbourseals (Phoca vitulina) con-tain high levels o regulatedPCBs and moderate levelso PBDEs. Te figure wasprepared using data romKrahn et al. (2007), Rayneet al. (2004) and Ross et al.(2000, 2012).

    WILDLIFEACROSSTHEGLOBEDISPLAYEDC-RELATEDREPRODUCTIVEEFFECTS.

    W P

    120

    100

    Population

    index(=1

    0

    0

    in

    1970)

    40

    80

    60

    1970 1975 1980 1985 1990 1995 2000

    Year

    Marine species

    Terrestrial species

    Freshwater species

    All vertibrate

    species (Living

    Planet Index)

    The Living Planet Index is anindicator of the state of the worldsbiodiversity. It measures trends inpopulations of vertebrate speciesliving in terrestrial, freshwater, andmarine ecosystems

    those exposed to lower concentrations. As levelso EDCs decline, some wildlie populations haveshown recovery. EDCs have affected immuneunction, resulting in increased susceptibility toinectious diseases in vertebrates, notably marinemammals. Taken together, the evidence shows thatexposure to endocrine disrupting contaminantsplays a significant role in wildlie health trends.

    350

    1.6

    1.2

    0.8

    0.4

    0

    250

    200

    150

    50

    100

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    300

    PCBs(mg/kglipid)

    PBDEs(g/kglipid)

    Killer whale Harbour seal

    Killer whale Harbour seal

    Immunotoxicity

    Transien

    t

    Southe

    rnresid

    ent

    North

    ernresid

    ent

    PugetS

    ound

    Strait

    ofGeorgia

    QueenC

    harlo

    tteStrait

    a

    b

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    12 S S E D C

    Hormones and EDCs that alter hormone actionscan act at all times during lieetal development,inancy, early childhood, puberty, adulthood andold age. Te timing o hormone or EDC action

    ofen determines the strength o their impact.In the adult, the hormone or EDC has an effectwhen it is present, but when the hormone or EDCis withdrawn, the effect diminishesmuch likeinsulin levels rising when blood sugar is high andthen declining when blood sugar declines.

    In contrast, exposure to hormones or EDCsduring development (in utero and inancy andearly childhood in humans) can have permanenteffects i the exposure occurs during the period

    when a specific tissue is developing. Tese effectsmay only become visible decades later. Tis iscalled developmental programming. Hormonescontrol the normal development o tissues romthe ertilized sperm and egg to the ully developedetus. Since some tissues continue developingafer birthsuch as the brain and reproductivesystemthe sensitive period or these tissuesis extended, sometimes or decades afer birth.

    Figure 14.Te effects oearly exposures to EDCsmay be maniested any timein lie.

    8. Sensitive periods for endocrine disruptoractionWindows of exposure

    When a tissue is developing, it is more sensitive tothe action o hormones and thus EDCs.

    Te mechanisms by which EDC exposure

    during development can alter the developmento specific tissues, leading to increasedsusceptibility to diseases later in lie, arejust beginning to be understood. It is clearthat hormones play an important role in celldifferentiation, which leads to the developmento tissues and organs. Once tissues and organsare ully developed and active, then hormoneshave a different role: to control the integrationo signals between tissues and organ systemsand to maintain normal unction. Early

    development (when hormones are controllingcell changes to orm tissues and organs) is thusa very sensitive time rame or EDC action. Ian EDC is present during the developmentalprogramming o a tissue, it could disrupt thenormal hormone levels, leading to changes intissue developmentchanges that would bestable across the lietime and possibly conersensitivity to disease later in lie. Tese effects

    Gestation Childhood Puberty Reproductive

    life

    Middle

    life

    Later

    life

    Exposures

    to EDCs

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    13

    Figure 15.Examples opotential diseases anddysunctions originatingrom early exposures toEDCs.

    are not likely to be evident at birth, but mayshow up only later in lie, rom a ew monthsto decades later (Figures 14 and15). Tesedevelopmental effects emphasize that babiesand children are not just little adults!

    Some EDCs produce effects that can crossgenerations (transgenerational effects), suchthat exposure o a pregnant woman or wild

    animal may affect not only the developmento her offspring but also their offspring overseveral generations. Tis means that the increasein disease rates we are seeing today could inpart be due to exposures o our grandparentsto EDCs, and these effects could increase overeach generation due to both transgenerationaltransmission o the altered programming andcontinued exposure across generations.

    S W

    Developm

    entalExposures

    Age(years)

    2 12 25 40 60 70

    Learning differences/Behaviour

    Asthma

    Increased sensitivity to infections

    Testicular dysgenesis syndromeAtherosclerosis

    Cardiovascular disease

    Infertility Breast cancer

    Obesity

    Altered puberty Fibroids

    Premature menopause

    Prostate cancer

    Alzheimer disease

    Parkinson disease

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    14 S S E D C

    Since 2002, a large number o chemicals otherthan POPs have been identified as EDCs, andthese include chemicals that have very differentproperties, sources and ates in the environment

    compared with POPs. EDCs are both manmadeand natural. Some are ound in a large variety omaterials, products, articles and goods. Tey mayalso be by-products ormed during manuacturingor combustion o wastes. Tese chemicals arealso subjected to biological and environmentaltransormations that may orm other EDCs.EDCs are ound among many classes ochemicals, including POPs, current-use pesticides,

    Figure 16.EDCs find theirway into the environ-ment via point and diffusesources, as illustrated here.

    9. Occurrence of and exposures to endocrinedisruptors

    phytoestrogens, metals, active ingredients inpharmaceuticals, and additives or contaminantsin ood, personal care products, cosmetics,plastics, textiles and construction materials. Once

    released into the environment, the more persistentchemicals can be carried by air and water currentsto remote locations, and many can be biomagnifiedthrough ood webs to high levels in humans andother top predators. Other chemicals have shorterliespans in the environment but are regularlyreleased in effluents, in agricultural runoff orrom urban environments, resulting in highenvironmental levels near the sources (Figure 16).

    Emissions tothe atmosphere

    Emissions tothe atmosphere

    Emissions torivers, lakes and oceans

    Sewage system to

    treatment facillity

    Chemicalproduction

    Industrialdischarges

    Untreatedwastewater Treatedwastewater

    Biosolidsapplication

    Incorporation intoconsumer products

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    15

    Wildlie and humans are exposed to EDCs inseveral different ways. Air, water, soil, sedimentand ood are sources o EDCs or wildlie.Human exposure to EDCs occurs via ingestiono ood, dust and water, via inhalation o gasesand particles in the air and through dermaluptake (Figure 17). Transfer of EDCs from thepregnant emale to the developing etus through

    the placenta and to offspring in mothers milk alsooccurs in both wildlie and humans. Children canhave higher exposures to EDCs because o theirhand-to-mouth activities. Tese multiple routes oexposure to a variety o EDCs mean that humansand wildlie are exposed to complex mixtures oEDCs. At this time, there are no data showinghow exposure to mixtures o virtually hundreds oEDCs at low concentrations will affect human and

    wildlie health. However, animal studies show thatexposures to mixtures o EDCs produce additiveeffects. Tese additive effects occur even wheneach chemical is present at low levels not shown toproduce effects individually. Tis means that manychemicals, each at levels without individual effect,could act together to cause health problems.

    Several hundred environmental pollutants havebeen measured in humans and wildlie aroundthe world, even in remote places such as theArctic. Levels o EDCs in humans and wildlievary with their location; some are higher in peopleand wildlie in urban or highly industrializedareas or sites where, or example, disposal oewaste occurs, whereas others are higher inremote environments because o long-range

    O

    Figure 17.EDCs rommultiple sources can betaken up by humans byseveral routes, enteringthe body via ingestion,inhalation and skin uptake.

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    16 S S E D C

    Figure 18.EDCs are oundin wildlie worldwide. Tisfigure shows concentrations(in ng/g wet weight) o per-fluorooctane sulonate, alsoknown as PFOS, in liver omarine mammals (modifiedrom Houde et al., 2011).

    transport by air and ocean currents and ood webaccumulation. A ew examples o exposure o

    wildlie around the world are shown in Figures18 and19. Tere are no longer any pristine areaswithout environmental pollutants. In addition,levels o chemicals in the body are tightly linkedto trends in their use. Tere are good exampleswhere bans or reductions in chemical use haveresulted in reduced levels in humans and wildlie.Indeed, human and animal tissue concentrationso many POPs have declined because thechemicals are being phased out ollowing globalbans on their use. In contrast, EDCs that arebeing used more now are ound at higher levelsin humans and wildlie. It is notable how wellproduction and exposure mirror each other, asexemplified in Figure 20.

    Hundreds o chemicals in commerce are knownto have endocrine disrupting effects. However,

    thousands o other chemicals with potentialendocrine effects have not been looked oror tested. It is likely that these chemicals arecontributing to wildlie and human exposuresto EDCs. Te situation is illustrated in Figure21. Since only a very limited number o allchemicals in commerce have been tested or theirendocrine disrupting properties, there may bemany more with such properties. Also, the EDCmetabolites or environmental transormationproducts and the by-products and productsormed upon waste treatment are not included inthese estimates, and their endocrine disruptingeffects are mainly unknown.

    1200

    1000

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    0

    ng/g wet weight

    Spotted seal

    Bearded seal

    Ringed seal

    Northern sea otter

    Southern seaotter

    Antarctic fur seal

    Harbour seal

    Harbourporpoise

    Harbourseal

    Harbourporpoise

    Finlessporpoise

    Baikal seal

    Indo-Pacificdolphin

    Minke

    whale

    Melon-headedwhale

    Long-beakedcommon dolphin

    Ganges river dolphin

    Franciscana

    dolphin

    Subantarctic fur seal

    Tucuxi dolphin

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    11. Testing for EDCsSince there are data rom epidemiologicalstudies showing associations between humandisease end-points and EDC exposures, it islikely that endocrine diseases and disordersare occurring at current exposure levels. Put

    another way, this means that there are situationsin which individually sae exposures o EDCshave reached a collectively harmul level or inwhich levels thought to be sae are not so.

    When chemicals are tested or endocrinedisrupting activity under specific validatedguideline studies, it is customary to examinethree doses to determine a level not apparentlyassociated with observable effects. Tis level,termed the no-observed-adverse-effect level, isthen divided by a so-called saety or uncertainty

    actor (o 100, or example) to extrapolate tolevels expected to be sae or humans or wildlie.Te doses declared sae are not actually tested,

    nor are the mixtures. Tese studies also assumethat there is a threshold or EDC effects, thatthere will be no effects at low doses and that thedoseresponse curve rises with increasing dose.As noted above, there is no threshold or EDC

    effects due to the presence o active hormonepathways, and EDCs are likely to have effects atlow doses. Consequently, their doseresponsecurves will not necessarily rise in proportionto dose. Regulatory guideline studies also focuson histopathology and organ and body weightsas the end-points. As noted above, EDCs cancause many diseases and affect many diseaseend-points that are not currently assessedin regulatory studies. Also, risk assessmentapproaches do not always assess toxicity duringdevelopment, which is the most sensitivewindow or EDC action, and also do not ollowthe animals or their lietime, which is needed toassess resulting diseases.

    T EDC

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    21

    POPs such as PCBs and DDT were banned inmany countries over 20 years ago due to theirenvironmental persistence and toxicity. As aresult, their levels in humans and wildlie havedeclined in recent decades. Bird populationsexposed to high levels of DDT, and in particularto its persistent metabolite, DDE, in the 1950sthrough 1970s in North America and Europe are,

    since 1975, showing lower concentrations of DDTand DDE and clear signs o recovery (Figure 22).However, there are studies showing that currentlow levels o these persistent chemicals are stillcausing harm, because they or their breakdownproducts remain in the environment long afertheir use has been banned.

    Lead is an important example o the cost oinaction in the ace o toxicity data. Lead hasbeen a known neurotoxicant since the Romantimes; nonetheless, it was used in gasoline andpaint around the world. Te impact o leadon children is proound, because it causesirreversible damage to developing bone and

    brain tissues. Te most damaging impact resultedrom the use o lead in gasoline, which caused anestimated intelligence quotient (IQ) loss o fivepoints in millions o children worldwide.

    Te ban on tetraethyl lead in gasoline occurredonly afer decades o inaction, when substituteswere available. Following the ban in the USA,

    lead levels in children ell dramatically, showingthat the ban had a huge impact on improvinghuman health (Figure 23).

    While this is an example o success, the scientificdata were present many years beore the policieswere changed and the chemical was banned.During that time, childrens health continuedto be harmed. So the question is, when arethere sucient data to act? Perhaps the answeris in making more use o the precautionaryprinciple to ban or restrict chemicals in orderto reduce exposure early, even when there aresignificant but incomplete data and beore thereis significant and long-lasting harm.

    Figure 23.Ban on lead ingasoline and the impact othis decision on childrensblood lead levels (basedon data rom the NationalHealth and NutritionExamination Survey in the

    USA).

    L

    20

    18

    Bloodl

    eadl

    evels(g/dl)

    Leadingasoline

    (to

    nnes)

    Year

    16

    14

    12

    10

    8

    6

    4

    2

    0

    227 000

    181 000

    136 000

    91 000

    45 000

    01970 1974 1978 1982 1986 1990 1994 1998 2002

    Leadedgasolinephaseout

    (1973)

    Blood lead levels

    Lead in gasoline

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    General aspects on endocrine disruption:Someendocrine disruptors can act directly on hormonereceptors as hormone mimics or blockers. Otherscan act directly on any number o proteins that

    control the delivery o a hormone to its normaltarget cell or tissue. Further, the anity of anendocrine disruptor to a hormone receptor isnot equivalent to its potency, and the chemicalpotency on a hormone system is dependentupon many actors. Also, endocrine disruptionrepresents a special orm o toxicity, and this mustbe taken into consideration when interpretingthe results o studies o EDCs or when designingstudies to clariy the effects o EDCs andquantiying the risks to human and wildlie health.

    Environmental chemicals can exert endocrinedisrupting activity on more than just estrogen,androgen and thyroid hormone action. Someare known to interact with multiple hormonereceptors simultaneously. Sensitivity to endocrinedisruption is highest during tissue development;developmental effects will occur at lower dosesthan are required or effects in adults. Hence,testing or endocrine disruption must encompassthe developmental period and include lielongollow-up to assess latent effects.

    Over the last 10 years, it has been establishedthat endocrine disruptors can work together toproduce additive effects, even when combinedat low doses that individually do not produceobservable effects. It has also become evident thatendocrine disruptors may produce non-lineardoseresponse curves both in vitro and in vivo, bya variety o mechanisms.

    Female reproductive health:Animal studieshave shown that EDC exposures during early

    development can cause altered mammary glandand uterine development, accelerated or delayedpuberty in emales, disruption o ertility cycles,fibroids and endometriosis-like symptoms.Tese effects are similar to those seen in humanpopulations, and it is reasonable to suspect thatEDCs are adversely affecting human emalereproductive health. Few studies have exploredthe role o EDCs and potential EDCs in causingemale reproductive health disorders. Most othe available evidence comes rom studies o

    adults rather than babies or children and ofenrom exposures to POPs. Understanding o thecontribution rom more modern chemicals hasonly recently expanded.

    13. Main conclusions and advances inknowledge since 2002

    Tere is much conflicting epidemiologicalevidence regarding the involvement o EDCsin premature puberty and breast development,menstrual cycles and adverse pregnancy outcomes

    (including preterm birth) in women. Tis ishardly surprising, considering the complexity orelating exposure measures to health outcomesrelative to the timing and duration o exposuresand including conounding actors such asmaternal age and weight and the quality oprenatal care. ere has been insucient studyo the relationship between EDC exposuresand polycystic ovarian syndrome or fibroids inwomen. Limited data link phthalate exposureswith increased fibroid prevalence. A number

    o studies have examined associations betweenexposure to chemicals and endometriosis,although most have measured exposure in adultlie. PCBs, dioxins and phthalates are implicated,although studies are sometimes conflicting.

    Historically high incidences o fibroids havealso occurred in seal populations in the BalticSea and have been associated with exposureto contaminants (particularly PCBs andorganochlorine pesticides). Recovery of thesepopulations is now occurring, ollowing a decline

    in the concentrations o these chemicals. Moreevidence now exists that reduced reproductivesuccess in emale birds, fish and gastropods isrelated to exposure to PCBs and dioxins. Asexposure to these EDCs decreased, adversereproductive effects in wild populations alsodecreased.

    Male reproductive health:Occupational oraccidental exposure o pregnant women toestrogen (DES) or to mixtures o EDCs thatinterere with male hormone action (e.g. anti-androgenic pesticides) increases the risk otesticular non-descent (cryptorchidism) intheir sons, causing reduced semen quality andincreased risk o subertility and testicular cancerin adult lie. No associations have been oundwith individual chemicals, underlining theimportance o including mixtures assessment inepidemiological and laboratory investigations.

    Cryptorchidism is sometimes ound togetherwith penile malormations (hypospadias).

    Limited evidence suggests a slightly increasedrisk o hypospadias or o reduced semen qualityassociated with exposure to mixtures o endocrinedisrupting pesticides. Limited evidence also

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    suggests links between maternal phthalateexposure and reduced anogenital distance (aproxy or reduced semen quality) in baby boys.For most chemicals, associations betweenetal exposure and childhood or adult malereproductive health have not been studied. Fewdata sets contain measures o chemical exposuresin pregnant women and o semen quality in their

    adult sons 2040 years later.

    Laboratory experiments with rats andepidemiological studies strongly suggest that theco-occurrence o cryptorchidism, hypospadias,testis germ cell cancer and impaired semen qualityis the result o reduced androgen action duringetal development, causing testicular dysgenesissyndrome. Using the rat model, a large andconvincing body o literature shows that a widerange o anti-androgenic and estrogenic EDCscan cause testicular dysgenesis syndrome in thelaboratory rat. Chemicals testing positive in thismodel include phthalate plasticizers and a range oanti-androgenic ungicides and pesticides. Limitedevidence also exists or the painkiller paracetamol.Effects o phthalates in the rat are not seen inthe mouse or in human testis ex vivo, and orbisphenol A (BPA), the human testis model ismore sensitive to toxic effects than the rat model.Better models o the human testis are needed oruse in chemical testing.

    With the exception o testicular germ cell cancers,which are logistically dicult to detect, symptomso androgen deficiency and estrogen exposure alsooccur in a variety o wildlie species in both urbanand rural environments and have been associatedwith exposure to chemicals in a limited numbero species in some areas. Te eminizing effectso estrogenic chemicals rom sewage effluents onmale fish was first reported in the 1990s and havenow been seen in many countries and in severalspecies o fish, indicating that this is a widespreadphenomenon. Feminized (intersex) male fishhave reduced sperm production and reducedreproductive success. Te suite o effects seen inwildlie can be reproduced in laboratory studiesin which experimental animals are exposed toestrogenic and anti-androgenic EDCs.

    Sex ratios:EDC-related sex ratio imbalances,resulting in ewer male offspring in humans, doexist as shown or 2,3,7,8-tetrachlorodibenzo-p-dioxin and 1,2-dibromo-3-chloropropane,although the underlying mechanisms are

    unknown. Also, EDC-related sex ratio imbalanceshave been seen in wild fish and molluscs, andthe effects o EDCs on sex ratios in some o thesespecies are also supported by laboratory evidence.

    Human fertility rates:Fertility rates are decliningall over the world, particularly in industrializedcountries. Although today we see stable, butageing, human populations in Japan and Europe,we shall soon see significant reductions in theirpopulations, as their ertility rates have been belowreplacement levels or 2040 years. Contraceptionand changes in social amily structures help

    explain these changes, although increasingreproductive health problems among men andwomen may also be important actors.

    Population declines in wildlife:Wildliespecies and populations continue to declineworldwide due to a number o actors, includingoverexploitation, loss o habitat, climate changeand chemical contamination. Given ourunderstanding o EDCs and their effects onthe reproductive system, it is extremely likely

    that declines in the numbers o some wildliepopulations (raptors, seals and snails) werebecause of the eects of chemicals (DDT, PCBsand tributyltin, respectively) on these species. Teevidence or POPs as a cause o these populationdeclines has increased now relative to 2002, dueto increases in these populations ollowing therestrictions on the use o these chemicals. EDCsin modern commerce with mechanisms o actionsimilar to those o POPs are suspected to also bea actor contributing to declines seen in wildliespecies today. Demonstrating a clear link between

    endocrine effects in individuals and populationdeclines or other effects will always be challenging,however, because of the diculty in isolatingthe effects o chemicals rom the effects o otherstressors and ecological actors. An endocrinemechanism or current wildlie declines isprobable but not proven.

    Tyroid health:Epidemiological evidence suggeststhat several groups o common contaminants,including PCBs, brominated flame retardants,

    phthalates, BPA and perfluorinated chemicals, areassociated with reduced serum thyroid hormonelevels in humans. Moreover, a much longer list ochemicals has caused a reduction in circulatinglevels o thyroid hormones or interered directlywith thyroid hormone action in experimentalanimals. Severe thyroid hormone deficiencycauses severe brain damage, such that universalscreening o thyroid hormone levels in serumoccurs all over the world. Moderate (25%) oreven transient insuciency of thyroid hormonesduring pregnancy is also associated with reduced

    IQ, ADHD and even autism in children andwith hypothyroid disorders in adults. Moreover,reduced serum thyroid hormone levels, although

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    still within population ranges classified as clinicallynormal, have been identified as risk actorsor increased serum cholesterol and elevatedblood pressure and reduced bone density inpostmenopausal women and so will be useulmeasures to investigate the relationship betweenchemical exposures and disease.

    Not all studies will find exactly the samerelationships between exposure and diseaseoutcomes due to the diculties in standardizingexposure measures and levels o hormonesrelative to the timing and duration o exposure.For thyroid hormones, levels are so variablebetween individuals that multiple measuresin the same individual would be required toestimate a set point with a precision o 5%.Tis known variability should be incorporatedinto study designs. Te issue is whether the

    correlations between contaminant exposureand various measures o endocrine unction areconsistent with effects on population health thatare mediated by effects on hormone action. Tecomplexity underlying the data is interpretedby some to indicate that there is no convincingevidence that chemicals can interere with thyroidhormone action in humans. Considering thatthere is strong evidence linking thyroid hormonelevels with adverse outcomes, particularly inchildren, precautionary approaches are necessary.

    Tere is strong evidence to conclude that thyroidhormones play the same role in brain developmentin both animals and humans. Tereore, rodentsare useul models or testing chemicals in orderto protect human populations rom additionalexposures. Te current set o validated testmethods and human clinical measures, however,considers changes in thyroid hormone levelsonly and needs to be improved to encompasschanges in thyroid hormone action. Tis meansthat there could be inconsistent relationships

    between exposure to thyroid disrupting chemicalsand measures o thyroid unction in humans, butvery strong evidence in animals indicating thatchemicals can interere with thyroid hormoneaction. Tis is certainly true or PCBs.

    Evidence o relationships between exposure tochemicals and thyroid hormone disruption inwildlie species has improved in the last decade,especially in relation to exposure to the flameretardant PBDEs and PCBs, but other chemicalshave been inadequately studied. Te strength o

    evidence supporting a role or EDCs in disruptingthyroid unction in wildlie adds credence to thehypothesis that this could occur in humans.

    Tyroid disruption is acknowledged to be poorlyaddressed by the chemical tests currently listed inthe Organisation or Economic Co-operation andDevelopment (OECD) conceptual ramework.Genetic lines o mice are now widely availablethat could help clariy the mechanisms by whichchemical exposures can interere with thyroidhormone action.

    Neurodevelopment:It is not widely appreciatedthat hormones play many critical roles inneurodevelopment, including the neuroendocrinecircuits that control sex-specific behaviour andphysiology, and thereore that EDCs could causea series o behavioural conditions and psychiatricdisorders that are evident in societies. Sucientdata indicate that in utero exposure to EDCsaffects cognition in animal studies, and limiteddata indicate that sexually dimorphic behavioursare also affected. Although some test guidelinesor developmental neurotoxicity have beendeveloped, no chemical testing strategies currentlyrequire evaluation o the ability o chemicals toproduce such effects.

    ere are sucient data in human populationsto conclude that high exposures to thyroiddisrupting PCBs during etal development (e.g.the children whose mothers ate contaminatedfish rom Lake Michigan or in the Yu-Cheng, oroil disease, children born to mothers exposed

    to PCBs) or to potential EDCs, such as lead andmercury, are linked to general cognitive problemsand alterations in sexual behaviour. Even relativelylow exposures, however, are associated withreduced cognitive unction. Te most consistentobservations are with impaired executiveunctioning, ollowed by processing speed, verbalability and visual recognition and memory.ADHD is overrepresented in children whosemothers had low thyroxine levels in the firsttrimester o pregnancy and in populations withelevated exposure to organophosphate pesticides,still ound in some populations. Tere is almost noinormation concerning the effects o mixtures oneuroendocrine disruptors, even though we knowthat they co-exist in human tissues. Data availablesuggest additive effects o different chemicals.

    Studies o exposed wildlie provide importantinormation on exposure levels, early andsubclinical effects and the clinical neurotoxicityo EDCs, because the mechanisms, underlyingeffects and outcomes o exposure are ofen similar

    to those in humans. Data showing effects ongrowth, development and behaviour in wildlieexist or some PCBs and mercury, but are sparseor non-existent or other EDCs.

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    Hormone-related cancers:Despite a great deal oresearch, the causes o most hormonal cancers area mystery. It is clear that hormones are requiredor the growth o cancerous tissues, but theirinvolvement in the earlier stages o carcinogenesis,through perhaps epigenetic effects, is unclear.Studies with animals now show that exposure tohormones (synthetic or natural) or EDCs (e.g.

    PCBs, PBDEs, dioxins, some organochlorinepesticides, BPA) during early development osome endocrine glands (e.g. breast, endometrium,prostate) can alter their development, perhapsthrough effects on stem cells, with possibleconsequences or susceptibility to cancer. Insome cases, cancer has been demonstrated inthese animals. In the thyroid gland, the existenceo stem cells has been hypothesized, but notdemonstrated. Although various chemicals havebeen shown to cause thyroid cancer in animals,

    current understanding o thyroid cancer does notlink it to an endocrine mechanism.

    Many poorly designed and conflicting studieshave arisen, until very recently, rom lack oknowledge that exposures must consider mixturesand must be measured beore the cancer appears,in etal development, in many cases. Tis meansthat, despite growing evidence that hormonesare risk actors or several endocrine cancers, ewepidemiological studies have shown links withEDCs. For breast cancer, the most convincing

    evidence appears to come rom associations withEDCs devoid o estrogenic activity, such as dioxinsand furans, for which sucient evidence exists. Forendometrial and ovarian cancer, very ew studieshave been carried out, and those that exist areconicting. For prostate cancer, sucient evidenceexists or an association with exposures to mixtureso pesticides in agriculture and in pesticidemanuacturing and to cadmium and arsenic,whereas evidence is conflicting or an associationwith PCB and organochlorine exposures. Many o

    the pesticides are acetylcholinesterase inhibitors,which also interere with metabolic conversiono hormones. Very many chemicals have notbeen investigated at all. For thyroid cancer,limited studies indicate higher rates in pesticideapplicators, although some o these also stem romiodine deficiencies in these people.

    Similar types o cancers o the endocrine organs,particularly reproductive organs, are also oundin wildlie species (several species o marinemammals and invertebrates) and in domestic pets.

    In wildlie, endocrine tumours tend to be morecommon in animals living in polluted regions thanin those inhabiting more pristine environments.

    Tere are many deficiencies in regulatorytesting methodologies for EDCs. Rodent strainsdeveloped or carcinogen testing were notdeveloped as models or the demonstrationo mammary cancer; an animal mammarycarcinogen may be a human carcinogen, but notnecessarily with the breast as a target organ. Otherrat strains not routinely used or testing would be

    more suitable or testing, but have hitherto beenused or only a handul o chemicals.

    Adrenal disorders:Numerous chemicals, mainlyPOPs, potentially affecting adrenal structure andunction have been described using in vitro assays,but no studies have investigated EDC associationswith adrenal hormone secretion in humans. Fewstudies have been carried out with laboratoryanimals. Te great majority o chemicals incommerce have not been tested.

    Bone disorders:It is well established that boneis a target tissue or estrogens, which affectbone mineralization and maturation. Very littleevidence, however, exists or effects o EDCs onthese processes, except in cases o accidental high-exposure incidents with hexachlorobenzene , PCBsand polychlorinated dibenzourans and in peopleeating contaminated fish rom the Baltic Sea.

    Metabolic disorders:Te control o metabolisminvolves many components o the endocrine

    system, including the adipose tissues, brain,skeletal muscle, liver, pancreas, thyroid glandand gastrointestinal tract. Tere are now animaldata showing that embryonic exposure to EDCsor potential EDCs (e.g. tributyltin, BPA, someorganochlorine and organophosphate pesticides,lead, perfluorooctanoic acid, phthalates) leads toaltered cholesterol metabolism, possible weightgain and type 2 diabetes in adulthood. Tere are nocompelling animal data linking chemical exposuresto type 1 diabetes, although some chemicals canaffect the unction o insulin-producing beta cells

    in the pancreas, including BPA, PCBs, dioxins,arsenic and some phthalates. Many o thesechemicals are also immunotoxic in animal models,and so it is plausible that they could act via bothimmune and endocrine mechanisms to cause type1 diabetes. Metabolic syndrome may also resultrom chemical exposures, although there has beenlittle study o this.

    Limited epidemiological data exist to support thenotion that EDC exposure during pregnancy can

    affect weight gain in inants and children. Limitedepidemiological data show that adult exposuresto some EDCs (mainly POPs, arsenic and BPA)are associated with type 2 diabetes, but there are

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    no data for type 1 diabetes, there is insucientevidence o endocrine mechanisms and there isinsucient study of this area in general.

    Immune disorders:It is increasingly clear thatEDCs likely play a role in the rise in immune-related disorders in both humans and wildlie.Many immune disorders have well-established

    ties to the endocrine system, such that disruptiono select endocrine pathways may disturb theimmune response, potentially causing allergies,endometriosis, bone disorders, autoimmunethyroid disease and immune cancers. Tis isbecause the immune and endocrine systemsare intricately connected through cross-talkbetween certain hormonal receptors and immunesignalling pathways. Sucient data now support arole for the lipid X receptor (LXR) and the steroidand xenobiotic receptor (SXR) in regulating whiteblood cell prolieration, and there are data linkinginflammation, immune dysunction and immunecancers with EDCs.

    Several studies with animals have demonstratedactivation or repression o receptor signallingpathways involved in immuneendocrineinteractions by organochlorine pesticides, PCBs,organotins, alkylphenols, phthalates, atrazine andBPA. Limited experimental and epidemiologicalevidence suggests that some PCBs, estrogens,atrazine and phthalates are developmental

    immunotoxicants, causing increased risk oinflammatory and autoimmune disorders. Tereare strong links, supported by animal studies,between phthalate exposure and the risingincidence o asthma. Endocrine mechanismsare highly plausible, but are not always provenor investigated. Together, these new insightsstress a critical need to better understand howEDCs affect normal immune unction andimmune disorders and how windows o exposuremay affect disease incidence (particularly orchildhood respiratory diseases).

    Human and wildlife exposures to EDCs:Tereis ar more knowledge on EDC exposure todaythan there was 10 years ago. Tis applies to thediversity o chemicals being implicated as EDCsand exposure routes and levels in humans andwildlie. As examples, brominated flame retardantswere mentioned only briefly and perfluorinatedcompounds not at all when the IPCS documenton EDCs was prepared 10 years ago (IPCS, 2002).In addition to these, there are now many more

    EDCs being ound in both humans and wildlie.Te most relevant main messages regardingexposure to EDCs are summarized below.

    Unlike 10 years ago, it is now better understoo


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