TOXINS: CREATING A SAFER TOMORROW

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TOXINS CREATING A SAFER TOMORROW

• Maricel V. Maffini, Ph.D
• Tufts University School of Medicine
• Wellesley (MA) 5/12/2009

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Theo Colborn, zoologist, writer
From the day of conception until an individual
is born or hatched, the development of each stage
of life is fully under the control of hormones.
Changes that happen during development are far
less reversible than those occurring in an
adult you can't go back and rewire the brain.
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Hormone-associated diseases/disorders

• Breast cancer
• Testicular cancer
• Prostate cancer
• Decrease quantity and quality of sperm
• Male genital tract defects (hypospadias,
  cryptorchydism)
• Infertility rates affects at least 11 of
  American couples of reproductive age (10 million
  couples). Causes 51 female, 49 male-associated

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The endocrine system

• - GROWTH
• - METABOLISM (FAT, SUGAR)
• - REPRODUCTIVE HEALTH
• LACTATION
• BRAIN DEVELOPMENT
• FETAL DEVELOPMENT
• PUBERTY

Testosterone Estrogen Progesterone Thyroid
Hormone Insulin Growth hormone Prolactin
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The endocrine system
Testosterone Estrogen Progesterone Thyroid
Hormone Insulin Growth hormone Prolactin

• - GROWTH
• - METABOLISM (FAT, SUGAR)
• - REPRODUCTIVE HEALTH
• LACTATION
• BRAIN DEVELOPMENT

Endocrine Disruptors
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The EPA definition
An endocrine disruptor is an exogenous agent
that interferes with the synthesis, secretion,
transport, binding, action, or elimination of
natural hormones in the body that are responsible
for the maintenance of homeostasis, reproduction,
development, and/or behavior.
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World Health Organization goes further

• 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.

Global assessment of the state-of-the-science of
endocrine disruptors. International Program on
Chemical Safety, World Health Organization
(2002).
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WHY ARE THESE CHANGES IMPORTANT?

• We are not exposed to single chemicals
• Time of exposure or windows of vulnerability
  (fetal development, puberty)
• Differential sensitivity
• Chronic exposure
• Effects can be carried through generations
• Declining in population(s) size, gender ratio,
  etc.

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EXAMPLES OF ENDOCRINE DISRUPTORS
NATURAL PHYTOESTROGENS ANIMAL HORMONES
SYNTHETIC/MAN-MADE DESIGNED CHEMICALS PETROLEOUM
BY-PRODUCTS

• Estrogen agonists/antagonists (DDT, BPA, DEHP,
  Parabens)
• Androgen agonists/antagonists (Vinclozoline,
  Phthalates)
• Thyroid disrupting agents (PCBs)
• Disruptors of hormone metabolism/synthesis
  (Atrazine)

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FRAGANCES, DETERGENTS
STORAGE, WRAPPING, PACKAGING
FLAME RETARDANTS
PESTICIDES, FERTILIZERS
SUNSCREENS
PLASTICS
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ENDOCRINE DISRUPTORS AND HUMAN HEALTH
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1976-SEVESO (ITALY)POPULATION EXPOSURE TO DIOXIN

• Cohort women who were infant to 40 years old at
  time of exposure
• Individual serum dioxin relates with breast
  cancer incidence
• Breast cancer risk increases with increase in
  serum dioxin

Warner et al. EHP, 2002
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1976-SEVESO (ITALY)POPULATION EXPOSURE TO DIOXIN

• Cohort women that were lt30 years old
• Women with higher levels of serum dioxin have
  higher risk of endometriosis

Eskenazi et al. EHP, 2002
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1976-SEVESO (ITALY)POPULATION EXPOSURE TO DIOXIN

• Cohort all women were premenopausal at the time
  of the explosion
• Statistically significant trend toward earlier
  menopause
• There is a nonmonotonic (inverted U-shape)
  dose-related association with increasing risk of
  earlier menopause

Eskenazi et al. EHP, 2005
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DDT

• Pesticide widely introduced in the USA in 1945,
  peak use in 1959
• Banned in 1972 (affected wildlife)
• Potent estrogen-mimic

Women under 20 years of age at the time of DDT
exposure have 5 times greater risk of developing
breast cancer
Many women heavily exposed in childhood have
not reached age 50
Cohn et al. EHP, 2007
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DES (diethylstilbestrol)
Given to between 2 and 10 million pregnant women
in the US between the years of 1948 and 1971.
DES treatment was banned in the US in 1971, but
continued to be used in other countries until the
1980s.
printed in the American Journal of Obstetrics
Gynecology in 1957.
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The DES daughters (1-2 million)

• Women with prenatal exposure to DES have an
  increased risk of breast cancer after age 40
  years (Palmer et al. Cancer Epidemiol Biomarker
  Prev, 2006)
• DES-exposed women were 50 more likely to
  experience menopause at any given age. This
  effect was dose dependent (Hatch et al. Am J
  Epidemiology, 2006)

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DES legacy

• Women exposed in utero developed a rare carcinoma
  of the vagina, had malformations of their genital
  tracts (H-shaped uteri), and abnormally shaped
  Fallopian tubes.
• Decreased ability to support pregnancy.
• Men exposed in utero had malformations of their
  genital tracts undescended testes, small testes,
  and cysts of the epididymus
• Their sperm quality was decreased and episodes of
  infertility increased.

Functional consequences of DES exposure became
evident after puberty
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OTHER HEALTH PROBLEMS ASSOCIATED WITH ENDOCRINE
DISRUPTORS EXPOSURE
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Pediatrics, American Academy of Pediatrics, 2008

• Data are sufficient to suggest a trend toward an
  earlier breast development onset and menarche in
  girls but not for other female pubertal markers.
• Current data for boys are insufficient to
  evaluate secular trends in male pubertal
  development
• - Altered puberty timing should be considered an
  adverse effect.

ADVANCED PUBERTY IN GIRLS
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Environmental Health Perspective, 2005

• The higher the levels of phthalates in the
  mothers urine, the shorter the ano-genital
  distance in boys. Anogenital is androgen
  dependent and is twice as long in males as in
  females
• - Boys with short AGD also had one or both
  testicles incompletely descended and a scrotum
  that was small or not distinct from surrounding
  tissue

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Environmental Health Perspective, 2007
- In this national cross-section of U.S. men,
concentrations of several prevalent phthalate
metabolites showed statistically significant
correlations with abdominal obesity and insulin
resistance - Our findings would suggest that
exposure to these phthalates may contribute to
the population burden of obesity, insulin
resistance, and related clinical disorders.
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PHTHALATE EXPOSURE

• Phthalates are widely used and can be found in
• Personal care use (makeup, shampoo, soaps)
• Plastics
• Paints
• Some pesticides

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ASSOCIATION OF URINARY BISPHENOL-A (BPA) WITH
MEDICAL DISORDERS

• Data from the National Health and Nutrition
  Examination Survey (NHANES) 2003-2004
• 1455 adults (age 18-74 years)
• urinary concentration of BPA
• markers of liver function
• glucose homeostasis
• inflammation
• lipid changes
• Higher urinary BPA was associated with
  cardiovascular diagnosis, diabetes, liver function

Lang et al. JAMA, 2008
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BPA in the American population
Calafat et al. Environmental Health Perspectives.
Available online Oct 24, 2007

• BPA was detected in the urine of 92.6 of the
  population (2,500 people tested)
• Children have higher levels than adolescents
• Adolescents have higher levels than adults
• Women have higher levels than men
• Non-hispanic whites and non-hispanic blacks have
  higher levels than Mexican-Americans
• High income households have lowest levels of BPA
  

gt
gt
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THE ORIGIN OF BPA
1891 CHEMIST SINTHESIZED BPA IN LAB
1930s DISCOVERED TO BE AN ESTROGEN, REPLACED BY
DES
1940s 1950s USED TO MANUFACTURE POLYCARBONATE
PLASTIC AND EPOXY RESINS
TO DATE COUNTLESS NUMBER OF CONSUMER PRODUCTS
CONTAIN BPA MULTIBILLION DOLLAR INDUSTRY
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BPA IS REGULATED BY US EPA
1988 A SAFETY STANDARD (OR REFERENCE DOSE) FOR
BPA WAS SET AT 50 MICROGRAMS/KILOGRAM BODY
WEIGHT/DAY THIS IS THE CURRENT DOSE CONSIDERED
SAFE
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Sources of BPA exposure

• Polycarbonate plastics
• Baby bottles
• Water bottles
• Water carboys, food containers
• Epoxy resins
• Dental sealants composites
• Lacquer coating of food cans (baby formula)
• Household glues, electrical insulation, water
  pipes,
• wine storage vats
• Human exposure
• Present in over 90 of urine samples analyzed by
  CDC
• Placenta
• Fetal plasma
• Amniotic fluid
• Ovarian fluid
• Breast milk

Chronic exposure to low environmental levels
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BPA AND BREAST CANCER
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THE MAJORITY OF BREAST CANCERS (90-95) ARE NOT
ASSOCIATED WITH FAMILY HISTORY OF BREAST OR ANY
OTHER CANCERS.
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1940
32
1960
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Hormones and breast cancer
There is one aspect of the disease everybody
agrees on an increased cumulative lifetime
exposure to endogenous estrogen increases the
risk of developing breast cancer

• Early age at menarche (lt12 years old)
• Late age at menopause (gt55 years old)
• Prenatal estrogen exposure (twin births vs
  pre-eclampsia)

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2007
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CRITICAL PERIODS DURING BREAST DEVELOPMENT
1- gestation 2- puberty
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WHY IS GESTATION A CRITICAL PERIOD?

• AN INDIVIDUAL IS BEEN FORMED
• EVERY ORGAN AND SYSTEM IN THE BODY IS FORMED (it
  takes 9 months in humans, 20 days in mice)
• COMPLEX COMMUNICATION NETWORKS ARE ESTABLISHED
• PERFECT AND EXQUISITE BALANCE OF HORMONES ARE
  NECESSARY
• TIMING IS KEY

IMBALANCES (TOO MUCH, TOO LITTLE, AT THE WRONG
TIME) HAVE LONG LASTING CONSEQUENCES THAT
MANIFEST AT DIFFERENT TIMES DURING THE
INDIVIDUALS LIFETIME
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WHY IS PUBERTY A CRITICAL PERIOD?
5 days
20 days
30 days
PUBERTY
The rodent mammary gland
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PUMP
- gestation - gestationlactation
PREGNANCY
BPA
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DOES BPA HAVE ANY EFFECT AT THE TIME OF EXPOSURE?
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Perinatal exposure to BPA
EFFECTS ON THE MAMMARY GLAND
NO-TREATED
1- accelerates the growth of
fetal mammary gland 2- fetal glands are
larger and longer 3-
certain aspects of development are
delayed
BPA-TREATED
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Perinatal exposure to BPA
EFFECTS ON THE MAMMARY GLAND 1- alterations in
shape and size can be seen at 1, 3, 4, 6, 9, 15
months of age 2- glands of virgin animals look
like those from pregnant ones
control 25ng BPA
250ng BPA
6 months 1 month
TD
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BPA exposure through lactation leads to dense
epithelium at 3 months
gestation
gestation lactation
control
250ng BPA
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Perinatal exposure to BPA
EFFECTS ON THE MAMMARY GLAND 1- mice developed
pre-cancerous lesions 2- rats developed carcinoma
in situ and pre-cancerous lesions
NO TREATMENT
BPA-TREATED MOUSE
BPA-TREATED RAT
NORMAL
PRE-CANCEROUS
CANCER
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BPA-exposed rats have increased tumor
susceptibility
BPA 250
BPA 2.5
BPA 1000
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Comparing the EPA safe dose with the
experimental doses
EPA safe dose 50 microgram/kg/day (50ug)
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WHAT CAN ANIMALS TELL US?

• 1981 Fetal DES exposure increased the propensity
  of the rat mammary gland to undergo neoplastic
  development.
• 2006 Breast cancer incidence is increased in
  women exposed in utero to DES.
• 2006 Prenatal exposure to BPA increases the
  vulnerability of the rat and mouse mammary gland
  to develop pre-tumoral lesions and carcinomas in
  situ.
• Will breast cancer incidence be found to
  increase in women exposed to BPA in utero in the
  next decades?

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BPA exposure and the link with breast cancer

• Increased mammary density
• Increased number of structures where cancers are
  thought to originate
• Increased sensitivity to estrogen
• Presence of intraductal hyperplasias and
  carcinomas in situ

Markey et al, 2001 Munoz de Toro et al,
2005 Wadia et al, 2007
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Effects of perinatal BPA exposure

• Advanced puberty
• Altered estrous cycles and early cessation of
  cyclic activity
• Altered ovarian morphology
• Quantitative changes on the expression of ERa and
  PR in the uterus
• Altered social, sexual and maternal behavior

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BPA AND THE BRAIN
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BPA AND THE BRAIN
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1. Defeminization of sexually dimorphic areas 2.
Increased male behavior
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Hyperactivity
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Obsessive behavior
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Effects of perinatal BPA exposure

• Increased prostate size
• Increased risk of prostate cancer
• Increased frequency of eggs with chromosomal
  aberrations
• Alters body weight
• Alters male infant behavior towards its mother
  (monkey)
• Interferes with spine synapse formation (monkey)

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What can we do?

• The easy things
• Avoid plastics and do not expose them to heat
• Minimize the consumption of canned food
• Buy organic food and hormone-free meats and dairy
• Wash fruits and vegetables thoroughly
• Use pesticide-free lawn care
• Choose eco-friendly cleaning products
• Reduce exposure of babies and young girls to
  personal care products (fragrances, cosmetics)

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WHAT CAN WE DO?

• Be informed
• www.cdc.gov/exposurereport
• www.cdc.gov/exposurereport/pdf/factsheet_phthalate
  s.pdf
• www.ewg.org/reports/infantformula
• www.ourstolenfuture.org
• www.silentspring.org
• http//sciencereview.silentspring.org/index.cfm
• www.ewg.org
• www.cosmeticsdatabase.com
• Ask questions
• Express your concerns

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SKIN DEEP COSMETIC SAFETY DATABASE
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SKIN DEEP COSMETIC SAFETY DATABASE
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What can we do?

• The hard things
• Use the precautionary principle

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Government of Canada Protects Families With
Bisphenol A Regulations News Release2008-167Octo
ber 17, 2008 The Government of Canada today
announced it will immediately proceed with
drafting regulations to prohibit the importation,
sale and advertising of polycarbonate baby
bottles that contain bisphenol A (BPA). The
Government will also take action to limit the
amount of bisphenol A that is being released into
the environment.
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What can we do?

• The hard things
• Use the precautionary principle
• Hold corporations accountable

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Sunoco restricts sales of chemical used in
bottlesBy MATTHEW PERRONE, AP Business Writer
Matthew Perrone, Ap Business Writer Thu Mar 12,
415 pm ETWASHINGTON Sunoco has begun
restricting sales of a controversial chemical
used in baby bottles and food containers that
some researchers believe can harm infants.The
move by the gas and chemical giant makes Sunoco
the first manufacturer to acknowledge safety
concerns about bisphenol-A, or BPA, which
recently led retailers like Wal-Mart to pull
thousands of baby and water bottles off store
shelves.In light of that uncertainty, Sunoco
said in a letter Thursday it has begun requiring
customers to guarantee that its BPA will not be
used in food and water containers for children
under 3."We will no longer sell BPA to
customers who cannot make this promise," Thomas
Golembeski, head of public relations, wrote in a
letter to two investors.
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Seeking Safer Packaging is a project of Green
Century Capital Management, Inc. (Green Century)
and As You Sow. The authors sent letters to 20
companies in the packaged food industry to
identify the actions the companies are taking to
address concerns regarding BPA. Fourteen
companies replied. Company scores are based
entirely on their responses to these letters.
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Our main findings include All companies
surveyed use BPA and are taking insufficient
steps to move toward alternatives. Hain
Celestial, Heinz, and Nestlé received the top
scores because all three companies are involved
in researching and testing of alternatives to BPA
and all have plans to phase out the chemical in
some products. Heinz stands out as a leader as
it is the only company surveyed that is currently
using an alternative to BPA in some of its can
linings. Three of the companies that responded
to our questions, Del Monte, Hershey, and J.M.
Smucker, are not taking action beyond monitoring
the industry to identify or implement
alternatives to BPA as a packaging material.
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What can we do?

• The hard things
• Use the precautionary principle
• Hold corporations accountable
• Change the way testing is done by regulatory
  agencies
• Develop better testing methods to assess total
  body burden

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UNIVERSITY OF GRANADA (SPAIN)CASE CONTROL STUDY

• The total xenoestrogen burden (combined load of
  xenoestrogens in fat measured by the E-SCREEN
  assay) correlates positively with breast cancer
  in post-menopausal women.

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What can we do?

• The hard things
• Use the precautionary principle
• Hold corporations accountable
• Change the way testing is done by regulatory
  agencies
• Develop better testing methods to assess total
  body burden
• Educate the public and health care professionals
  about risks and ways to prevent unnecessary
  exposures
• Start talking about prevention

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Bisphenol A Toxic Plastics Chemical in Canned
Food Companies reduced BPA exposures in Japan
(http//www.ewg.org/node/20938)
Environmental Health Perspective, 2003
Changes in the composition of can coating
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The National Toxicology Program Report

• In April 2008
• The NTP concurs with the conclusion of the CERHR
  Expert Panel on bisphenol-A that there is some
  concern for neural and behavioral effects in
  fetuses, infants, and children at current human
  exposures. The NPT also has some concern for
  bisphenol-A exposure in these populations based
  on effects in the prostate gland, mammary gland,
  and an earlier age for puberty in females
• In June 2008
• The levels of concern for effects on the mammary
  gland and puberty were downgraded to minimal

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The U.S. Food and Drug Administration Report

• In April 2008, the FDA task force released the
  following statement
• Based on our ongoing review, we believe there is
  a large body of evidence that indicates that
  FDA-regulated products containing BPA currently
  on the market are safe and that exposure levels
  to BPA from food contact materials, including for
  infants and children, are below those that may
  cause health effects.

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The U.S. Food and Drug Administration Report

• Fall 2008, a FDA Scientific Advisory Subcommittee
  released the following statement
• Coupling together the available qualitative and
  quantitative information (including the
  application of uncertainty factors) provides a
  sufficient scientific basis to conclude that the
  margins of safety defined by the FDA as
  adequate are, in fact, inadequate

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August 14, 2008 WASHINGTON, D.C. President
Bush signed a federal bill today that bans six
toxic phthalates from childrens products. The
measure is officially known as the Consumer
Product Safety Improvement Act of 2008 Six
types of phthalates, chemicals linked to genital
defects in males, have been banned from toys
along with lead. The phthalate provision makes
three phthalates permanently illegal and three
others temporarily illegal until the CPSC can
determine whether the chemicals are safe or
dangerous.http//www.consumeraffairs.com In
2007, California, Washington and Vermont
restricted phthalate use in childrens products.
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Mar 16, 2009 Suffolk County Unanimously Passes
First BPA Baby Bottle Bill Suffolk County, NY,
has become the first jurisdiction in the nation
to ban bisphenol A in baby bottles and sippy
cups. The countys legislature passed the ban
with a unanimous vote on Tuesday. April 3,
2009 Suffolk County Executive Steve Levy
announced this afternoon that he has signed the
first in the nation ban on the sale of empty
beverage containers (baby bottles and cups)
containing Bisphenol-A.
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March 17th, 2009 BPA Ban Introduced U.S.
Lawmakers Follow Canada and Europe in Outlawing
Toxic Plastic Chemical United States lawmakers
have taken the first steps toward banning the use
of a toxic chemical blamed for causing
developmental problems in children from baby
bottles and other beverage containers. Two bills
have been introduced into the House of
Representatives and the Senate to establish a
federal ban on bisphenol A (BPA) in all food and
beverage containers. The legislation has not yet
been debated or subjected to a vote. The new
bills, sponsored by Rep. Edward Markey (D-Mass.)
and Sens. Dianne Feinstein (D-Calif.) and Chuck
Schumer (D-N.Y.), follow various efforts to limit
the use of BPA in baby bottles.
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ttp//www.nytimes.com/2009/05/10/nyregion/connecti
cut/10bpact.html?_r1refpolicy Measure to
Restrict BPA Moving to State Senate        
        By MARGARET FARLEY STEELE Published May
6, 2009 Under the Connecticut legislation,
infant formula and baby food stored in cans,
plastic containers or jars containing BPA could
no longer be made or sold in the state as of
October 2011. Baby bottles, sippy cups and
reusable food and beverage containers like sports
bottles with BPA would also be phased out. Other
food containers that use BPA liners, including
most canned goods, would have to carry a
conspicuous warning on the label.
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Acknowledgements
Beverly Rubin
Carlos Sonnenschein
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Rachel Carson biologist, writer, ecologist
(1907-1964)
On April 3, 1963, the Columbia Broadcasting
System's television series "C.B.S. Reports"
presented the program "The Silent Spring of
Rachel Carson." In it, Miss Carson said "It is
the public that is being asked to assume the
risks that the insect controllers calculate. The
public must decide whether it wishes to continue
on the present road, and it can do so only when
in full possession of the facts.