Recent Advances on the Impact of Endocrine Disruption 2014-04-22آ  Recent Advances on the Impact of

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  • Recent Advances on the Impact of Endocrine

    Disruption

    Åke Bergman Stockholm 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

    SOS of EDCs - 2012

  • UNEP/WHO report 2002 UNEP/WHO report 2012

    State of the science of EDCs - Global reports

    SOS of EDCs - 2012

  • 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

    SOS of EDCs - 2012

    Hormone systems and hormones

  • Ten years ago!

    EDCs = A few Persistent Organic Pollutants

    Dioxins (PCDDs/Fs)

    PCBs

    DDTs

    HCB

    (PBDEs mentioned)

    SOS of EDCs - 2012

  • 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

    SOS of EDCs - 2012

  • Low dose effects

    and

    Non-monotonic dose-response relationships

    SOS of EDCs - 2012

  • Mixture effects of EDCs

    SOS of EDCs - 2012

  • Risks related to windows or exposure

    Early prenatal

    week 1-16 Late 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)

  • D e

    ve lo

    p m

    en ta

    l Ex

    p o

    su re

    Learning differences/Behaviour Astma

    Increased sensitivity to infections Testicular dysgenisis syndrome

    Infertility Breast cancer

    Obesity

    Altered puberty Fibriosis Premature menopaus

    Atherosclerosis Cardiovascular disease

    Prostate cancer Alzheimer disease Parkinson disease

    2 12 25 40 60 70

    Age (Years)

    Developmental exposure to endocrine disruptors

    manifested later in life

    SOS of EDCs - 2012

  • 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

    SOS of EDCs - 2012

  • 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.

    SOS of EDCs - 2012

  • EDCs and female reproductive health

    Diethylstilbestol (DES) – the most well- known chemical affecting female reproductve health

    SOS of EDCs - 2012

    Bisphenol A (BPA) – estrogenic compound but 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

    Human PCOS, fibroids, endometriosis

    (PCB), ovarian failure, poor

    pregnancy outcome, early breast

    development.

    Likely a role for EDCs, but

    supporting epidemiological and

    experimental evidence is limited

    Wildlife Imposex (TBT)

    eggshell thinning (DDE)

    fibroids (PCB)

    reproductive failure (PCB)

    SOS of EDCs - 2012

  • 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).

    Human Testicular Dysgenesis Syndrome:

    chryptorchidism, hypospadia,

    germ cell cancer.

    Poor semen quality

    Rodent studies Sufficient evidence supporting that androgen insuffficiency during

    embryonic/fetal development could cause these reproductive

    disorders, and that environmental EDCs can contribute.

    Wildlife Some evidence from wildlife

    populations for reproductive

    developmenlal disorders and

    low semen quality, realted to

    EDC contamination (OCs,

    PBDE, steroidal estrogens)

    SOS of EDCs - 2012

  • Prevalence in hypospadias

    among newborn Danish

    boys, 1977-2005

    SOS of EDCs - 2012

  • Endocrine disruptors and hormone related cancers

    SOS of EDCs - 2012

  • Endometrial cancer rates, worldwide

    SOS of EDCs - 2012

  • Proposed relationship: Endometrial cancer risk vs. Protective factors

    SOS of EDCs - 2012

  • 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

    SOS of EDCs - 2012

  • Incidence of testicular cancer worldwide

    SOS of EDCs - 2012

  •  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 endocrine disrupting chemicals.

    Strength of evidence: EDCs and Cancer

  • Endocrine disrupting chemicals and sex ratio

    in humans and wildlife

    SOS of EDCs - 2012

    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

    Procloraz Female

    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