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We Are What We Eat

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Title: We Are What We Eat


1
We Are What We Eat?
  • Emily J. Dulude, MD
  • Pediatric Conference
  • January 9th, 2004

2
Case 1
  • You are seeing a new patient of Dr. Reiter in
    Endocrine Clinic during your elective month, who
    recently moved here from Puerto Rico. As you are
    wrapping up your interview and exam, the parents
    ask you if the reason that little six year-old
    Ana has begun to develop breasts is related to
    the smokestacks in their hometown.

3
Case 2
  • You are at your second site clinic in lovely
    Northampton. The mother of a 5 year old girl
    named Star asks you if the organic, free-range
    beef she buys at the local Whole Foods market has
    been subjected to growth hormone, and if so, what
    are the dangers to her child?

4
  • What do you say to these parents?
  • Before you can answer THEIR questions,
  • you need to answer a few of YOUR OWN!

5
Your Questions
  • Question 1
  • What the HECK are they talking about?
  • Question 2
  • WHY havent I been taught this stuff during my
    medical training???

6
Its called Environmental Pediatrics
7
Timeline The Evolution of Environmental
Pediatrics
  • 1988 Formation in of a National Academy of
    Sciences (NAS) Committee on Pesticides in the
    Diets of Infants and Children
  • 1995, the Environmental Protection Agency (EPA)
    categorized and initiated formal research of
    EDCs within the emerging field environmental
    endocrine research
  • 1996 Food Quality Protection Act (FQPA),
    unanimously passed by Congress, which requires
    that pesticides be regulated to protect infants
    and young children from their acute and chronic
    adverse health effects
  • 2001 the Ambulatory Pediatric Association (APA)
    established a new national fellowship training
    program in Environmental Pediatrics.

8
A Changing Environment
  • The environment of children today is different
    from 50 years ago.
  • More than 80,000 synthetic chemicals, nearly all
    of them invented since World War II
  • Children especially at risk for exposure to the
    2800 of these chemicals that are produced in
    quantities of more than 1 million tons per year
  • These high-production-volume (HPV) chemicals are
    distributed widely in the environment--in air,
    food, water
  • Only 43 of the HPV chemicals have been tested
    for their potential to cause toxicity, and fewer
    than 20 for their capacity to interfere with
    children's development.

9
and the Changing Face of Disease
  • Major diseases confronting children in the United
    States and in other industrially developed
    nations today are no longer infectious, but
    chronic illnesses of multifactorial origin
  • asthma, doubled in frequency since 1980
  • birth defects, the leading cause of infant death
  • developmental disorders, such as attention
    deficit hyperactivity disorder and autism
  • childhood leukemia and brain cancer, increased in
    incidence since the 1970s
  • Although genetic factors are thought to account
    for 10 to 20 of cases of chronic disease in
    childhood, most of the causes of these diseases
    are unknown.
  • It is strongly suspected that some pediatric
    diseases are caused at least in part by exposures
    to environmental toxins.

10
Implications for Children
  • Because of children's rapid growth and
    development and their physiologic and cognitive
    immaturity, they have greater exposure and
    greater vulnerability to biological, chemical,
    and physical environmental hazards compared with
    older age groups.

11
The Child At Risk
12
A Sordid History of Environmental Exposures in
Children
  • 1904 Queensland, Australia First report of lead
    paint poisoning in children
  • 1940-50 Hiroshima and Nagasaki Epidemic of
    leukemia in young children exposed to radiation
    in atomic bombings
  • 1960s Japan Mercury poisoning in children who
    ate contaminated fish (CP, MR, seizures). The
    mercury came from a nearby plastics factory.

13
1970s Diethylstilbestrol (DES) A Breakthrough
Discovery
  • DES was prescribed to women from 1948-1971, to
    prevent spontaneous abortions
  • Vaginal cancer and other reproductive tract
    anomalies were discovered in the offspring of
    mothers taking DES during pregnancy

14
DES and the Discovery of a New Environmental
Hazard
  • DES was also being given to cattle to promote
    growth- an estimated 13 tons of DES was being
    dumped into the environment through
    feedlots/waste
  • This stimulated thought that other estrogenic
    chemicals found in the environment may directly
    impact human endocrine function.
  • These chemicals were subsequently dubbed
    endocrine disrupting chemicals (EDCs)

15
The New Kid On the Block Endocrine Disrupting
Chemicals
  • What are endocrine disrupting chemicals (EDCs)?
  • How do they exert their action on humans?
  • What studies are out there to support the
    relationship between EDCs and clinical outcomes
    in humans?
  • How has the discovery of EDCs impacted U.S.
    governmental regulation of food and drugs?
  • Why do I ask so many questions?

16
Endocrine Disrupting Chemicals (EDCs)
  • Definition
  • An exogenous agent that interferes with the
    synthesis, storage/release, transport,
    metabolism, binding, action or elimination of
    natural blood-borne hormones responsible for the
    regulation of homeostasis and the regulation of
    developmental processes. (Whoa)
  • Many EDCs have estrogenic properties
    (xenoestrogens), and are thought to exert their
    effects by acting on estrogen receptors

17
EDCs and Steroid Receptor Promiscuity
  • Many chemicals classified as environmental
    estrogens can bind to more than one type of
    steroid receptor
  • This may have evolutionary implications
  • Examples o,p-DDT (a pesticide) can bind to both
    estrogen and progesterone receptors with similar
    affinities
  • Other compounds may equally inhibit binding to
    estrogen, androgen, and progesterone receptors

18
EDCs and Hormone Receptor Interaction
19
The Bottom Line
  • EDCs are proposed to be responsible for
  • Cancer cause and prevention!
  • Precocious puberty
  • Infertility
  • Gender predetermination in offspring
  • Reproductive tract deformities
  • Learning disabilities in children
  • Cholesterol disorders
  • Brittany Spears recent Vegas wedding

20
Where are these chemicals found?(You can run,
but you cannot hide)
  • Pesticides (DDE, DDT)
  • Pharmaceuticals (DES in past)
  • Industries plastics factories, ex.(phthalates)
  • Naturally occurring (yams!phytoestrogens)
  • Electrical systems/insulators (PCBs)
  • They are everywhere, folks.

21
Endocrine Disruptors and the EPA
  • Categories of EDCs
  • Phenols/alkylphenols
  • DES
  • Dioxins
  • Cadmium
  • Fungicides/herbicides/pesticides
  • Mercury,metals,lead
  • Organochlorines
  • PCBs
  • Phthalates
  • Phyoestrogens
  • And Others!

22
EDCs and Biomagnification
  • Many EDCs are persistent organic pollutants-
    lipophilic, man-made chemicals highly resistant
    to degradation
  • Distributed in varying quantities throughout the
    world
  • Bioaccumulate in the food chain, and stored in
    fatty tissues efficiently
  • Biomagnification up the food chain results in
    potential widespread human exposure
  • Makes in vitro and in vivo assays challenging due
    to unquantifiable levels of these chemicals

23
EDCs Estrogenic
  • Major culprits are compounds suspected of
    interfering with the normal action of estrogen
    through its receptor (estrogen agonists and
    antagonists)
  • Environmental compounds with estrogenic activity
    have been shown to masculinize the female
    rodents brain, inducing precocious puberty
    (centrally)- ex. DES
  • Phytoestrogens (legumes) shown to induce an
    infertility syndrome (clover disease in sheep),
    but may protect against breast cancer (high
    concentrations in urine of Asian women)

24
EDCs Androgenic
  • Compounds with anti-androgenic properties shown
    to inhibit androgen activity in developing,
    pubertal and adult male rats and in the alligator
    population in Florida, with resultant feminized
    steroid profiles
  • Vinclozolin (a fungicide) metabolite M2 in vivo
    studies in male rats born without penis
  • pp-DDE (metabolite of dichlorodiphenyltrichloroet
    hane, or DDT, an organochlorine pesticide) spill
    into Florida lake in 1980s- infertile alligators
  • Male pesticide applicators in Minnesota Red River
    Valley had decreased mean total testosterone
    concentrations, and increased numbers of female
    offspring vs. male offspring compared to controls

25
EDCs and the Decline in Male Reproductive Health
(sorry, guys)
  • Decrease in human sperm count and altered sperm
    motility/morphology since 1940s
  • Increase in developmental reproductive anomalies
    hypospadias, cryptorchidism, testicular/prostate
    cancers
  • However, the link to EDCs is tenuous at best

26
Non-sex steroid receptor mediated EDCs
  • Thyroid function (impaired TH activity)- PCBs
  • Learning disabilities in children exposed to high
    levels of polychlorinated biphenyls (PCBs-
    produced in US 1929-1972) in cord blood or breast
    milk
  • Cholesterol metabolism
  • B-sitosterol in fish lowers gonadal steroid
    production by possibly altering cholesterol
    availability/reducing P450 activity
  • Norepinephrine synthesis
  • Disulfiram inhibits NE synthesis and affects
    ovulation and pregnancy outcomes in rodents,
    birds, and humans
  • GnRH and LH release
  • Chloroatrazine inhibits pulsatile release of GnRH
    and LH and induces pseudopregnancy, and may
    contribute to development of mammary gland tumors
    in rat models

27
Some Interesting Studies(I kid you not)
  • Endocrine disruption in sexual differentiation
    and puberty. What do pseudohermaphroditic polar
    bears have to do with the practice of
    pediatrics?Gulledge CC - Pediatr Clin North Am -
    01-OCT-2001 48(5) 1223-40

28
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29
DDT and Precocious Puberty in Children Migrating
from Developing Countries
  • DDT (insecticide) behaves as an estrogen agonist
    /or androgen antagonist banned from use in US
    and Western Europe since late 1960s, but still
    used extensively in developing countries
  • Its metabolite pp-DDE (half-life several
    decades) found in high levels in serum of
    foster/adopted children migrating from developing
    countries with precocious puberty compared to
    native Belgian children
  • DDE found to accelerate GnRH pulsatile secretion
    in immature rat
  • Migration from the country of origin may
    interrupt DDT exposure, and central precocious
    puberty may result from withdrawal of negative
    feedback effects of sex steroids (DDT)

30
Withdrawal hypothesis of central precocious
puberty after prepubertal exposure to sex steroids
31
Premature Thelarche in Puerto Rican Girls
  • Background Puerto Rico has the highest known
    incidence of premature thelarche ever reported.
    Organic pollutants (pesticides, phthalate
    esters-plasticizers, both known EDCs) have been
    widely used in P.R.
  • Design 41 serum samples from premature thelarche
    patients compared with 35 controls, analyzed by
    GS/MS for pesticides and phthalates, metabolites
  • Results Very high levels of phthalates in 68
    samples from thelarche patients, levels in only
    one control
  • Conclusion Possible relationship between
    phthalate EDCs and premature thelarche in human
    females

32
Remember Case 1?
  • Maybe Anas parents are on to something!
  • How do we field parents questions?
  • because the link between EDCs and clinical
    outcomes is so tenuous, we can only discuss the
    possibility of it with parents more research is
    badly needed.

33
As For Case 2Bovine Growth Hormone
  • After more than 10 years of intense
    investigational research of BGH, the FDA approved
    its use in 1993
  • Studies in 1950s concluded that bovine GH
    preparations are not effective in humans
    (species-specific)- biologically inactive in
    humans
  • BGH is not orally active in rats nor humans
  • Milk nutritional composition from cows injected
    with rbST is unchanged 90 of rbST in milk is
    destroyed with pasteurization
  • Insulin-like growth factors (IGF-1) content found
    in rbST-treated cows milk is no different than
    that found in human breast milk, and rIGF-1 is
    not active
  • Despite its safety, beef without BGH is available
    and is labeled as such.

34
Resources for Pediatricians
  • http//www.epa.gov
  • American Academy of Pediatrics Handbook of
    Pediatric Environmental Health. Washington, DC,
    AAP, 1999
  • (A.K.A. The Green Book)
  • Covers topics such as asbestos, asthma, carbon
    monoxide, dietary supplements/ethnic remedies,
    endocrine disruptors, smoking, powerlines,food
    contaminants, lead, indoor air pollutants,
    mercury, breast milk(!), noise, pesticides, UV
    light, radon.

35
Barriers to Sound Research of EDCs
  • 1. President Bush
  • 2. President Bush
  • 3. President Bush
  • 4. Quantifiable levels of toxins difficult to
    measure (biomagnification)
  • 5. Inadequate surveillance by public health
    programs
  • 6. Complex biological systems and interactions to
    prove cause and effect
  • 7. Industries may suffer cash-ola lost for big
    business

36
Future Directions
  • National Childrens Study (2000)
  • US Congress set up funds for cohort study of as
    many as 100,000 children followed prospectively
    until at least 18 years old, to examine the
    effects of environmental toxins on childrens
    health
  • It is anticipated that the preliminary results
    from the first years of the study will be
    available in 2008-2009.

37
NCS
38
Hey 3rd and 4th Years! Need a Job?
  • PROGRAM OFFICER POSITIONNational Children's
    Study (NCS)Rockville, Maryland
  • Description of Duties and ResponsibilitiesThe
    Program Office of the National Childrens Study,
    DESPR, is conducting a national search for a
    qualified candidate to serve as a program officer
    for development of a large cohort study of
    environmental effects on childrens health and
    development, as part of a federal multi-agency
    effort.This is to be a very large national
    multi-center study of approximately 100,000
    children and their families followed from before
    birth to adulthood.This position is expected to
    support the scientific planning, implementation
    and analysis and reporting of the study. For more
    information about the proposed study, see the web
    page at http//www.nationalchildrensstudy.gov.
    Duties will include synthesizing scientific data,
    writing study protocols, scientific supervision
    of NCS research projects, interpretation and
    reporting of results.
  • Qualifications include a Ph.D. in a field closely
    related to topics of concern for the study or an
    M.D. with appropriate additional epidemiological
    experience or training (e.g. an M.P.H. or
    equivalent).

39
Quiz Time
  • Question 1
  • Of the 2800 chemicals produced in high volumes
    (HPVs), what percentage have been tested for
    their effects on the development of children?
  • A. 5
  • B. 20
  • C. 40
  • D. 60
  • E. Testing is not necessary after all, arent
    children just little adults?

40
And the Answer Is
  • B. 20

41
Quiz Time
  • Question 2
  • Major chronic childhood diseases confronting
    industrialized nations, with suspected links to
    environmental toxins include all of the following
    except
  • A. Asthma
  • B. Birth defects
  • C. Autism
  • D. Leukemia
  • E. Coprophagia

42
And the Answer Is
  • E. Coprophagia
  • (ingestion of excrement)

43
Quiz Time
  • Question 3
  • Which of the following factors place children at
    higher risk than adults to the effects of
    environmental toxins?
  • A. Young age
  • B. Cognitive immaturity
  • C. Physiologic immaturity
  • D. Rapid growth
  • E. All of the above

44
And the Answer Is
  • E. All of the above

45
Quiz Time
  • Question 4
  • True or False
  • Endocrine disrupting chemicals have been shown
    through careful scientific research to be
    responsible for precocious puberty.

46
And the Answer Is
  • False

47
Quiz Time
  • Question 5
  • All of the following are ways in which WE as
    pediatricians can expand both the public and
    professional understanding of pediatric
    environmental health
  • a. Apply now for a fellowship in Environmental
    Pediatrics
  • b. Support politicians who are advocates of
    pediatric environmental health research
  • c. Be politically active in local environmental
    awareness programs
  • d. Peer-review an AAP professional journal on
    pediatric environmental health
  • e. Of course, all of the above

48
And the Answer Is
  • E. All of the above

49
References
  • Colon I. Identification of phthalate esters in
    the serum of young Puerto Rican girls with
    premature breast development. Env Health
    Perspectives. 2000 108(9) 895
  • Cooper RL. Endocrine disruptors and reproductive
    development a weight-of-evidence overview. J
    Endocr. 1997152 159
  • Epstein SS. Potential public health hazards of
    biosynthetic milk hormones. Internat J Health
    Services. 1990 20(1) 73
  • Etherton TD. Recombinant bovine and porcine
    somatotropin safety and benefits of these
    biotechnologies. J Am Diet Assoc. 1993 93 177
  • Garry VF. Male reproductive hormones and thyroid
    function in pesticide applicators in the Red
    River Valley of Minnesota. J Toxicol Environ
    Health. 2003 66(11) 965
  • Juskevich J. Bovine growth hormone human food
    safety evaluation. Science. 1990 249 875
  • Parent A . The timing of normal puberty and the
    age limits of sexual precocity variations around
    the world, secular trends, and changes after
    migration. Endocr Rev. 2003 24(5)668
  • Solomon G. Extra ingredients hormones in food.
    Env Health Perspectives. 199410 632

50
The End
51
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52
Growth Hormone for Animal Agriculture? No way!
  • Mass resistance by US consumers to use of
    recombinant bovine somatotropin (rbST) and
    porcine somatotropin (rpST) in the 1990s due to
  • Overall mistrust of FDA (ex- DES disaster)
  • Domination of synthetic hormone research by
    industry
  • Failure of industries (Monsanto, ex) to disclose
    their unpublished data
  • Manipulation of published data
  • Their refusal to label milk and meat from cows
    treated with biosynthetic hormones
  • Reduction in number of small dairy farms due to
    economic takeover by industries utilizing rbST
    technology

53
Back to our Case for a moment
  • So maybe she is right!
  • Growth hormone is evil- a plot by our government
    to make money on beef!

54
The History of Recombinant Bovine Growth Hormone
  • In 1930s, injection of dairy cows with bovine
    pituitary extracts increased milk yield, and was
    eventually attributed to bovine growth hormone,
    or bovine somatostatin
  • Limited supply of and impurity of
    pituitary-derived bovine growth hormone precluded
    its commercial use on farms
  • 1980s- advent of biotechnology allowed mass
    production of pure bST through recombinant DNA
    processes

55
Recombinant Bovine and Porcine Somatotropin
(rbST, rpST)
  • bST
  • Increases milk production in cows by 15-20
  • Improves productive efficiency by 10 (kg milk/kg
    feed)
  • pST
  • Increases growth rate by 10-20 in pigs
  • Improves productive efficiency by 15-35
  • Markedly increases muscle mass while reducing fat
    by as much as 80

56
Safety of rbST in Humans The Debate Laid to Rest
  • After more than 10 years of intense
    investigational research of rbST, the FDA
    approved its use in 1993
  • Studies in 1950s concluded that bovine GH
    preparations are not effective in humans
    (species-specific)- biologically inactive in
    humans
  • bST is not orally active in rats nor humans
  • Milk nutritional composition from cows injected
    with rbST is unchanged 90 of rbST in milk is
    destroyed with pasteurization
  • Insulin-like growth factors (IGF-1) content found
    in rbST-treated cows milk is no different than
    that found in human breast milk, and rIGF-1 is
    not active
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