Title: We Are What We Eat
1We Are What We Eat?
- Emily J. Dulude, MD
- Pediatric Conference
- January 9th, 2004
2Case 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.
3Case 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!
5Your Questions
- Question 1
- What the HECK are they talking about?
- Question 2
- WHY havent I been taught this stuff during my
medical training???
6Its called Environmental Pediatrics
7Timeline 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.
8A 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.
9and 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.
10Implications 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. -
11The Child At Risk
12A 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.
131970s 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
14DES 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)
15The 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?
16Endocrine 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
17EDCs 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
18EDCs and Hormone Receptor Interaction
19The 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
20Where 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.
21Endocrine Disruptors and the EPA
- Categories of EDCs
- Phenols/alkylphenols
- DES
- Dioxins
- Cadmium
- Fungicides/herbicides/pesticides
- Mercury,metals,lead
- Organochlorines
- PCBs
- Phthalates
- Phyoestrogens
- And Others!
22EDCs 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
23EDCs 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)
24EDCs 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
25EDCs 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
26Non-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
27Some 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(No Transcript)
29DDT 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)
30Withdrawal hypothesis of central precocious
puberty after prepubertal exposure to sex steroids
31Premature 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
32Remember 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.
33As 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.
34Resources 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.
35Barriers 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
36Future 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.
37NCS
38Hey 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).
39Quiz 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?
40And the Answer Is
41Quiz 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
42And the Answer Is
- E. Coprophagia
- (ingestion of excrement)
43Quiz 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
44And the Answer Is
45Quiz Time
- Question 4
- True or False
- Endocrine disrupting chemicals have been shown
through careful scientific research to be
responsible for precocious puberty.
46And the Answer Is
47Quiz 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
48And the Answer Is
49References
- 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
50The End
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52Growth 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
53Back 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!
54The 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
55Recombinant 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
56Safety 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