Recent Advances on the Impact of Endocrine
Disruption
Åke BergmanStockholm University, Stockholm, Sweden
An endocrine disruptor is an exogenous substance or mixture that
alters function(s) of the endocrine system and consequently causes
adverse health effects in an intact organism, or its progeny or
(sub)populations (IPCS 2002)
or
An EDC is an exogenous chemical or mixture of chemicals that
interferes with any aspect of hormone action
(The Endocrine Society, 2012)
Definitions of Endocrine Disruptors
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UNEP/WHO report 2002 UNEP/WHO report 2012
State of the science of EDCs - Global reports
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Around 50 hormone systems
with around 100 signalling
compounds.
Systems in focus so far:
Estrogens, Androgens and
Thyroid hormones - EAT
Hormone systems well
preserved between species
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Hormone systems and hormones
Ten years ago!
EDCs = A few Persistent Organic Pollutants
Dioxins (PCDDs/Fs)
PCBs
DDTs
HCB
(PBDEs mentioned)
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HERBICIDES
2,4,-D
2,4,5,-T
Alachlor
Amitrole
Atrazine
Linuron
Metribuzin
Nitrofen
Trifluralin
FUNGICIDES
Benomyl
Ethylene thiourea
Fenarimol
Hexachlorobenzene
Mancozeb
Maneb
Metiram - complex
Tri-butyl-tin
Vinclozolin
Zineb
METALS
INSECTICIDES
Aldicarb
beta-HCH
Carbaryl
Chlordane
Chlordecone
DBCP
Dicofol
Dieldrin
DDT and metabolites
Endosulfan
Heptachlor / H-epoxide
Lindane (gamma-HCH)
Malathion
Methomyl
Methoxychlor
Oxychlordane
Parathion
Synthetic pyrethroids
Transnonachlor
Toxaphene
INDUSTRIAL CHEMICALS
Bisphenol - A
Polycarbonates
Butylhydroxyanisole (BHA)
Cadmium
Chloro- & Bromo-diphenyl
Dioxins
Furans
Lead
Manganese
Methyl mercury
Nonylphenol
Octylphenol
PBDEs
PCBs
Pentachlorophenol
Penta- to Nonylphenols
Perchlorate
PFOA
p-tert-Pentylphenol
Phthalates
Styrene
Testosterone synthesis inhibitor Estrogen receptor agonist
Thyroid hormone disruptor Androgen receptor antagonist
Industrial byproducts
Heavy metals
Surface protectors
Plastics
Plasticizers
Pharmaceuticals Additives
POPs Flame Retardants
Herbicides
Personal Care products/Cosmetics
> 800 EDCs
Pesticides
EDCs have many sources
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Low dose effects
and
Non-monotonic dose-response relationships
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Mixture effects of EDCs
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Risks related to windows or exposure
Early prenatal
week 1-16Late prenatal
week 17-40
Postnatal
Birth -25 years
Early Prenatal Mid-Late Prenatal Postnatal
Week 1-16 Week 17-40 Birth – 25 years
Central nervous system (3wks - 20 years)
Ear (4-20 wks)
Kidneys (4-40 wks)
Heart (3-8)
Immune system (8-40 wks; competence & memory birth-10yrs)
Limbs (4-8wks)
Lungs (3-40 wks; alveoli birth-10yrs)
Reproductive system (7-40wks; maturation in puberty)
Skeleton (1-12 wks)
De
velo
pm
enta
lEx
po
sure
Learning differences/BehaviourAstma
Increased sensitivity to infectionsTesticular dysgenisis syndrome
Infertility Breast cancer
Obesity
Altered puberty FibriosisPremature menopaus
AtherosclerosisCardiovascular disease
Prostate cancerAlzheimer diseaseParkinson disease
2 12 25 40 60 70
Age(Years)
Developmental exposure to endocrine disruptors
manifested later in life
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1.4 million wildlife species
Feminisation of wild fish
Thyroid, immune &
reproductive disorders in
many wildlife species
Biodiversity loss – also an effect influenced by EDC
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Key Concerns
Three strands of evidence fuel concerns
over endocrine disruptors:
o the high incidence and the increasing trends
of many endocrine-related disorders in
humans;
o observations of endocrine-related effects in
wildlife populations;
o the identification of chemicals with endocrine
disrupting properties linked to disease
outcomes in laboratory studies.
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EDCs and female reproductive health
Diethylstilbestol (DES) – the most well-known chemical affecting femalereproductve health
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Bisphenol A (BPA) – estrogenic compoundbut less potent compared to DES
Female reproductive system- Strength of evidence
Reproductive disorders prevalent in some human and wildlife populations. Laboratory studies give sufficient evidence that several environmental chemicals can give rise to such disorders
HumanPCOS, fibroids, endometriosis
(PCB), ovarian failure, poor
pregnancy outcome, early breast
development.
Likely a role for EDCs, but
supporting epidemiological and
experimental evidence is limited
WildlifeImposex (TBT)
eggshell thinning (DDE)
fibroids (PCB)
reproductive failure (PCB)
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Male reproductive system – Strength of evidence
Sufficient evidence that reproductive disorders originating during fetal life are increasing in human populations.
Limited evidence linking these disorders to EDCs (pesticides, PBDE, phthalates).
HumanTesticular Dysgenesis Syndrome:
chryptorchidism, hypospadia,
germ cell cancer.
Poor semen quality
Rodent studiesSufficient evidence supporting that androgen insuffficiency during
embryonic/fetal development could cause these reproductive
disorders, and that environmental EDCs can contribute.
WildlifeSome evidence from wildlife
populations for reproductive
developmenlal disorders and
low semen quality, realted to
EDC contamination (OCs,
PBDE, steroidal estrogens)
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Prevalence in hypospadias
among newborn Danish
boys, 1977-2005
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Endocrine disruptors and hormone related cancers
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Endometrial cancer rates, worldwide
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Proposed relationship: Endometrial cancer risk vs. Protective factors
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Trends in the incidence of
prostate cancer in selected
Countries, world-wide
USA Japan Canada
Republic of Korea India
Australia
France
Ireland
The Netherlands
United Kingdom
Denmark
Finland
Sweden
Norway
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Incidence of testicular cancer worldwide
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There is sufficient evidence that the incidence of most hormonal cancers has increased or remains at a high level, and that environmental exposures play a role in these trends.
Several independent studies have shown associations between PCDD/F exposures and elevated breast cancer risks.
There is also sufficient evidence for increased breast cancer risks among women with elevated PCB exposures and a Cyp polymorphism.
Sufficient evidence exists for a link between pesticide exposures during application and manufacture.
One epidemiological study has demonstrated a link between internal estrogen burden from lipophilic chemicals and breast cancer.
Single epidemiological studies have shown associations between DDT and endometrial cancer, and between triazine pesticides and ovarian cancer.
There is thus far no evidence linking thyroid cancer with any endocrinedisrupting chemicals.
Strength of evidence: EDCs and Cancer
Endocrine disrupting chemicals and sex ratio
in humans and wildlife
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Among the highest TCDD exposed parents in Seveso
81 children were born
50 girls
31 boys
Significant correlation to TCDD levels in the fathers
17β-Estradiol
Trenbolone
ProclorazFemale
Male
Sex ratio disturbance in
zebra fish exposed to
EDCs
Endocrine disruptors and thyroid related disorders and diseases
Incidence rate of CH in New York State (NYS), 1987–
2007, and in the United States (excluding NYS), 1987–2006.
Birth prevalence of congenital hypothyroidism (CH)
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WildlifeLimited evidence from wildlife and sufficient evidence from animal experiment that EDCs can interferewith thyroid hormone signalling, leading to disease and disorders in
wildlife species
HumanSufficient evidence that somethyroid diseases increase, relatedto environmental exposures
Sufficient evidence linking PCB tocognitive deficiency in children
Insufficient data linking chemicalexposures to altered hormonesignalling and disease/ dysfunction
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Thyroid – Strength of evidence
Endocrine disruptors and neurodevelopment
in children and wildlife
Prevalence of ADHD
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• Increased evidence for thyroid hormone mechanisms in brain disorders
in humans and wildlife.
• Increased evidence of the great sensitivity of embryonic and postnatal
development to EDCs when compared with adults.
• Increased number of studies showing a relationship between cognitive
function and chemical exposures in humans. These studies however are
often weakened by the nature of the study designs, and more prospective
studies are warranted.
• First evidence of subtle effects of methylmercury and bisphenol A on
reproductive behaviors of wildlife individuals that may be of relevance to
populations.
Endocrine disruptors and neurodevelopment
Scientific progress since 2002
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HumanAdrenocortical degeneration/necosis (o,p’-DDD)
Covalent binding ex vivo, in vitro (cell line)
Decreased hormone synthesis
(o,p’-DDD, MeSO2-DDE)
Lab animalAdrenocortical degeneration/necosis, bioactivation and
Inhibited hormone secretion (MeSO2-DDE, DDD; mouse) HPA axis (PCB; sheep)
WildlifeAdrenocortical hyperplasia; Baltic seal (PCB/DDT, MeSO2-DDE?)
Covalent binding/necrosis, decreased hormone synthesisin vivo/vitro (MeSO2-DDE) in mink/otter/bird/fish
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Adrenal cortex; HPA axis
Endocrine disruptors and metabolic disorders
Obesity development
in a few countries
globally
Diabetes T1 ad T2
Metabolic syndrome
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Endocrine disruptors and immune function, immune
diseases, and disorders in humans and wildlife
There is sufficient evidence that EDCs play a role in the development of
immune-related disorders and are at least partially responsible for the
increase in these diseases in recent years
There are substantial data linking systemic inflammation, immune dysfunction
and immune cancers such as lymphoma and leukemia with EDCs
There is good evidence that EDCs acting through nuclear hormone receptor
pathways can directly affect the HPA axis, particularly through their actions on
the adrenal glands
There are good epidemiological data linking PAH, PCBs and other persistent
POPs with autoimmune thyroid disease
There are sufficient data linking exposure to phthalates, PCBs and dioxins
with endometriosis
There are strong links between EDC exposure, particularly phthalates, and the
rising incidence of asthma throughout the developed world
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Endocrine
System
Nervous
System
Immune
System
Neuro-
Endocrine-Immune
network
Slide kindly provided by Prof. Xiaodong Cheng, Tongji Univ. Shanghai
The 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 difficult to identify.
Despite these difficulties, some associations have become
apparent.
Key Concern
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Future needs
Strengthening knowledge of EDCs
Improved testing for EDCs
Identifying EDCs
Reducing exposures and thereby vulnerability to disease
Creating enabeling environments for scientific advances, innovation and disease prevention
Methods for evaluating evidence
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Acknowledgement goes to
UNEP and WHO for their
initiative, contributions
intellectually and financially.
It also goes to the Working
group members and the
external authors as well as
the reviewers of the report
Merci!
The Working Group (Editors underlined)
Georg Becher, Norwegian Institute of Public Health, NorwayÅke Bergman, Stockholm University, Sweden (Leader)Poul Bjerregaard, University of Southern Denmark, DenmarkRiana Bornman, Pretoria Academic Hospital, South AfricaIngvar Brandt, Uppsala University, SwedenJerrold J. Heindel, National Institute of Environmental Health Sciences, USATaisen Iguchi, National Institutes of Natural Sciences, Okazaki, JapanSusan Jobling, Brunel University, EnglandKaren A. Kidd, University of New Brunswick, Canada
Andreas Kortenkamp, University of London and Brunel University, EnglandDerek C.G. Muir, Environment Canada, CanadaRoseline Ochieng, Aga Khan University Hospital, KenyaNiels Erik Skakkebaek, University of Copenhagen, DenmarkJorma Toppari, University of Turku, FinlandTracey J. Woodruff, University of California at San Francisco, USAR. Thomas Zoeller, University of Massachusetts, USA
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Bruce Blumberg, University of California, Irvine, USA
Jayne V. Brian, Brunel University, England
Stephanie C. Casey, University of California, Irvine, USA
Heloise Frouin, Institute of Ocean Sciences, Fisheries and
Oceans, Canada
Linda C. Giudice, University of California, San Francisco,
USA
Monica Lind, Uppsala University, Sweden
Erik Ropstad, Norwegian School of Veterinary Science,
Oslo, Norway
Peter S. Ross, Institute of Ocean Sciences, Fisheries and
Oceans Canada
Laura N. Vandenberg, Tufts University, Medford, USA
Additional contributing authors
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UNEP and WHO representatives
From UNEP, Chemicals Branch
Timothy J Kasten (Head)
Agneta Sundén-Byléhn
Nida Besbelli
From WHO, Department of Public Health and Environment
Maria Neira (Director)
Marie-Noël Bruné Drisse
Ruth A. Etzel
Hard copies available from UNEP, Geneva; Please email:
Or from the web site:http://www.who.int/ceh/publications/endocrine/en/index.html
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