Monday Mar 20th

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Monday Mar 20th Hormonal Influences from the
Chemical Environment Endocrine Disruptors -
exogenous substances or mixtures that alter
function of the endocrine system and consequently
cause adverse health effects in an intact
organism, or its progeny (European
Commission,1996).
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• Well-established increased incidence of feminized
  or masculinized fish, amphibians, reptiles, birds
  with respect to anatomy and reproductive
  behaviors.
• Concerns about the role of endocrine disruptors
  in human disease
• Decreased sperm quality
• Increased cryptoorchidism, hypospadias, and
  altered anogenital distance
• Effects on sex ratio
• Increased testicular cancer
• Increased prostate cancer
• Increased breast cancer
• Increased endometriosis
• Effects on fertility
• Effects on cognition and behavior

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• Early human reports that have raised
  environmental concerns
• aviation crop-dusters handling DDT (old
  pesticide) reported to have reduced sperm counts
  (1949)
• industrial workers at plants producing
  chlordecone (kepone a chlorinated hydrocarbon
  pesticide) were reported to have lost their
  libido, become impotent and to have low sperm
  counts (70s)
• experiments in laboratory animals demonstrated
  the estrogenic activity of those pesticides
  (1982).
• man-made compounds used in the manufacture of
  plastics reported to be estrogenic (1991) -
  nonylphenol and bisphenol-A.
• more recent reports about phthalate plasticizers
  also anti-androgenic
• Reports on PCBs and thyroid disruption
• DES, an old drug used to prevent miscarriage was
  reported to cause adverse effects in offspring
  (1971)

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• The endocrine, reproductive, and behavioral
  effects of these chemicals are believed due to
  their ability to
• Mimic the effect of endogenous hormones
• Antagonize the effect of endogenous hormones
• Disrupt the synthesis and metabolism of
  endogenous hormones
• Disrupt hormonal synthesis
• Disrupt hormonal transport
• Disrupt the synthesis of hormone receptors.
• Most notably estrogens androgens thyroid

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• Role of Estrogens Females
• Sexual maturation
• Menstrual cyclicity
• Bone development and continued growth and
  maintenance
• Metabolism of fats
• Regulate certain aspects of blood clotting
  (relevant to arteriosclerosis)
• Believed relevant to many aspects of feminine
  behavior and abilities

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• Role of Estrogens Males
• Normal bone development
• Certain aspects of male reproductive development
  (androgens converted to estrogens in brain)
• Spermatogenesis
• Other physiological effects perhaps relevant to
  prostate cancer

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• Role of Androgens Males
• many aspects of male reproductive development
• Male sexual maturation
• Spermatogenesis
• Sex drive
• Many aspects of behavior and abilities
• Role of androgens Females
• Female sex drive
• May influence some aspects of female cognitive
  ability

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• Role of Thyroid Hormones
• Regulate metabolism
• During early development, control certain aspects
  of brain development relevant to intelligence,
  sensory function, and motor functioning

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• Primary route of average human exposure to
  endocrine disruptors - contaminated food and
  water
• In workplace or certain professions, exposures
  may come via inhalation or through skin.
• Early concerns about unintended effects on
  endocrine system drug
• Concerns about environmental chemicals quickly
  followed

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I. Diethylstilbestrol (DES)

• Potent nonsteroidal estrogen
• First synthesized in 1938

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• 19381971DES and similar nonsteroidal estrogens
  marketed under many brand names
• Combined with progesterone
• Combined with androgens
• Vaginal creams and suppositories
• Oral administration
• Injections
• Many different doses and regimens used

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• 19381971
• Total number of women and exposed fetuses not
  known with certainty
• An estimated 510 million women and their fetuses
  exposed in the US

Guisti RM, et al. Ann Intern Med 1995.
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• Women Prescribed DES While Pregnant
• Modestly increased risk for breast cancer
• A significantly increased risk (RR gt 2) has been
  disproved
• No evidence for other adverse effects at this time

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• DES Daughters (estrogen prenatally present at a
  time when it should not be)
• Increased risk for a wide range of abnormalities
  involving the Müllerian-derived internal
  structures and upper tract
• Clear cell adenocarcinoma of the vagina and
  cervix
• Genital malformations
• Infertility
• Adverse pregnancy outcomes
• Possible increased risk of cervical dysplasia
• Despite increased risks of infertility and
  adverse pregnancy outcome, most DES Daughters can
  become pregnant and carry a pregnancy to term
• Pregnancies in DES Daughters are managed as high
  risk pregnancies

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• DES Daughters at later ages?
• In their 4th and 5th decade of life, the risk of
  clear cell adenocarcinoma (CCA) of the vagina and
  cervix still exists, but appears to be low
• No other known increased risks of malignancy at
  this time
• Further follow-up is needed

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• DES Sons
• Increased risk for epididymal cysts
• Some studies indicate increased risks for other
  genital abnormalities
• Most DES Sons have no discernible abnormalities
• Research is ongoing on risks for testicular
  cancer
• No demonstrated risks for other cancers

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• II. Endocrine Disruptors Phthalates
• Dialkyl or alkyl/aryl esters of
  1,2-benzenedicarboxylic acid (7 primary ones)
  toxicity varies greatly across individual esters
  and mixtures
• Used in plastics and other consumer products
• increase flexibility in plastics
• softeners in skin care products
• medium to hold fragrances, colors
• Found in perfumes, hairsprays and cosmetics,
  construction materials, wood finishes, adhesives,
  floorings, and paints, PVC plastics.
• Also found in retainers used in orthodontic
  dentistry certain dental composites nipples on
  baby bottles tubing used in medical devices
  blood bags liquid food bags tubing for blood
  transfusions, ventilation air bags timed
  released medications.
• Ingestion, inhalation, and dermal exposure
  throughout life.

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Widely found in environment leach out of the
plastics and other products 18 billion pounds
used/year DEHP is the most common phthalate 2
million tons/year EPA sets tolerable daily limit
(TDL) for DEHP 20 micrograms/kg body
weight/day Avg US adult exposures 3-30
micrograms/kg/day (avg is below TDL) More than
90 from food contamination (plastic packaging,
use of PVC gloves in meal preparation) If
receiving certain medical trts or working in
certain occupations, may get 450/kg/day Infants/
toddlers get 50 from food and the rest from
ingesting dust from toys, bottles, etc.
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2003
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Worst are oils and fats, cheeses, poultry
products, processed meats.
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Effects in Adult Animals (most studies on
DEHP) Carcinogens and liver toxicants Reproduct
ive toxicants in male rats, mice, ferrets, and
guinea pigs when administered orally effects on
sperm counts, motility, and morphology effects
on fertility reduced testosterone
production Data from female adult animal studies
not conclusive some studies indicate reduced
fertility reduced estrogenic activity others do
not.
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Effects in Adult Humans Phthalates found in
most adult urine samples and blood samples, as
well as breast milk, and infant
samples. Carcinogenic effects are
controversial. Inadequate human data.
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• Animal Developmental Toxicity Findings (oral
  administration)
• intrauterine death
• malformations skeletal (tail, limb, digits)
  eye abnormalities neural tube defects
  (exencephaly)
• abnormalities in male reproductive tract
  anatomical, cellular, physiological
• developmental delay

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Developmental Effects - Human 1. Levels found in
umbilical cord blood have shown that higher
levels ? shorter pregnancy durations. 2. Urinary
levels in pregnant women are associated with
reduced anogenital distance in male infants (Swan
et al, 2005). Problem levels found in 25 of
American women. 3. Inadequate/absent data on
other concerns.
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Lines represent the average anogenital distance
at each age. Boys with higher collective
exposures had shorter distances.