Toxic Chemicals in the Daily Environment

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Toxic Chemicals in the Daily Environment

• Reducing Chronic Diseases and DisordersThrough
  Safer Solutions

Ted Schettler MD, MPH Science and Environmental
Health Network www.sehn.org
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Health
environment
Poverty Racism Stress Access to health
care Social support Nutrition Toxic
chemicals Radiation Infections Physical agents
Genes and environment are in continuous conversa
tion Environmental factors can alter gene
function, gene expression
genes
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Status of Developmental Toxicity Testingfor the
2,863 ChemicalsProduced Above 1 million
pounds/year
Some Data On Developmental Toxicity
30 Tested for Neurodevelopmental Toxicity Accor
ding to EPA Guidelines
No Data On Developmental Toxicity
In Harms Way, www.preventingharm.org
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Chemicals in consumer products

• Many different potential health effects e.g.
  asthma cancer birth defects altered fetal,
  infant, child, development infertility, etc.
• Level, timing, duration of exposure are
  important windows of vulnerability
• Susceptible sub-populations for a variety of
  reasons e.g. multiple, cumulative exposures
  associated stressors life stage genetic
  determinants, etc.

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This presentation

• Focus on one chemical (bisphenol A) used in many
  different consumer products
• An example of a more general set of issues
• Ubiquitous exposures
• Increasingly well studied instructive with
  respect to toxic properties
• Policy implications and options

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Bisphenol A

• First synthesized in late 19th century
• Determined to be estrogenic in 1920s
• Polymerized in polycarbonate plastic and also
  used in some resins and flame retardants
• Annual global production gt 6 billion pounds

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Bisphenol A uses

• food and drink packaging
• CDs and other hard plastics
• lacquers that coat metal products such as food
  cans, bottle tops, and water supply pipes.
• polyester resins, polysulfone resins,
  polyacrylate resins, flame retardants.
• processing of polyvinyl chloride plastic and in
  the recycling of thermal paper.
• Some polymers used in dental sealants and tooth
  coatings contain bisphenol A

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Bisphenol Aexposures

• Widespread in general population
• 93 of representative study population have
  detectable levels of BPA in urine (NHANES,
  included no children less than 6 yrs old)
• Levels higher in children than adults
• Male median 1.63 ng/ml urine
• Female median 1.12 ng/ml urine

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Bisphenol A--exposures

• Childhood exposure estimates
• Most studies estimate 2-20 microgm/kg/day from
  dietary sources for infants and young children
• (CERHR, 2008)

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Bisphenol A metabolism

• Bisphenol A absorbed from intestinal tract
• Metabolism involves glucuronidation, which
  renders the BPA less active and facilitates
  excretion
• A debate about the speed with which this occurs
  and whether free BPA is in the blood has been
  featured in scientific literature
• Fetus and infant have undeveloped glucuronidation
  capacity

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Bisphenol A at everyday levels
Human, (free BPA)
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BPA in blood and breast milk
CERHR, Natl Toxicol Program, 2008
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Fig. 2. Concentrations (in ng/ml) of unconjugated
BPA in plasma in female mouse pups throughout the
24 h after a single dose, administered either
orally (solid line) or by subcutaneous injection
(dashed line). BPA was administered at either
35microg/kg (low dose, circles) or 395microg/kg
(high dose, squares). Values represent mean
plasma values at each time point (S.E.M.). Note
the log scale for the Y-axis. (Taylor et al.
Repro Toxicology, 2008)
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Bisphenol Atoxicity

• Estrogenic activity through classic estrogen
  receptor has received considerable attention
• We now know that BPA can also act through other
  receptors and other mechanisms, including
  modifying thyroid hormone status
• Concentrate here on low dose effects

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Health questions about BPA
Impaired brain development
Hyperactivity
Aneuploidy Downs
Prostate, breast cancer
Low sperm count
Long-term memory formation
Dementia
Obesity and diabetes
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BPAbreast cancer

• Peri-natal exposure to environmentally relevant
  doses of BPA (subcutaneously)mice
• Female offspring with increased number of
  terminal end buds in mammary glands and decreased
  apoptosis (programmed cell death) intraductal
  hyperplasia

Vandenberg et al Repro Toxicol
2008 Munoz-de-Toro Endocrinology 2005
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BPAbreast cancer

• Miceneonatal and pre-pubertal exposure to BPA
  via lactation resulted in increased numbers and
  shorter latency of tumors in mammary glands of
  female offspring after exposure to a carcinogen
  (DMBA) in adulthood
• Various proteins associated with cell
  proliferation and decreased apoptosis upregulated
  in adults (Jenkins, EHP, 2009)

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BPAprostate cancer

• Miceprenatal exposure to environmentally
  relevant doses of BPA causes proliferation of
  ducts and prostatic intraepithelial neoplasia in
  male offspring
• Ratsperinatal exposure to BPA increases
  precancerous lesions and susceptibility to
  hormonally related adult prostate cancer (Prins,
  2008)

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BPA--aneuploidy

• Micelow level BPA exposure interferes with
  chromosomal separation during cell division
  resulting in aneuploid cells (abnormal numbers of
  chromosomes in daughter cells)
• (Hunt, Curr Biol, 2003)

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Aneuploidy cell division gone wrong
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Bisphenol A causes aneuploidy
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Bisphenol A causes insulin resistance in mice
Rapid response 30 min after addition of BPA or
estradiol Blood sugar drops because insulin
increased
Slower response After 4 days BPA-treatment,
insulin increases but animals no longer respond
Alonso-Magdalena EHP, 2006 Ropero, Intl J
Androl, 2008
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Bisphenol Adiabetes, humans

• Higher BPA concentrations were associated with
  diabetes (OR per 1-SD increase in BPA
  concentration, 1.39 95 confidence interval
  CI, 1.21-1.60 P lt .001)
• NHANES population-wide survey
• (Lang et al. JAMA 2008)

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Bisphenol Aheart disease, human

• Higher urinary BPA concentrations were associated
  with cardiovascular diagnoses in age-, sex-, and
  fully adjusted models (OR per 1-SD increase in
  BPA concentration, 1.39 95 confidence interval
  CI, 1.18-1.63 P .001 with full adjustment).
• NHANES representative population
• (Lang, et al. JAMA 2008)

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Bisphenol A suppresses adiponectin release from
human adipose tissue (in vitro explants)
Adiponectin is a hormone that protects against
insulin resistance, metabolic syndrome,
inflammation.
Hugo, Environ Health Perspect 2008
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Bisphenol Abrain

• Many studies of developmental exposures to BPA in
  rodents and impacts on behavior
• Decreased response to novelty increased general
  activity in females
• in all different experimental settings, while a
  significant sex difference was observed in the
  control group, exposure to BPA decreased or
  eliminated the sex difference in behavior
• Associated with altered levels of
  neurotransmitters in sexually dimorphic brain
  areas

(Palanza Environ Res, 2008)
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Bisphenol Abrain

• exposure of ovariectomized young adult nonhuman
  primates to BPA at 50 microg/kg/d
• completely abolishes the synapse-forming
  effect of estradiol in all hippocampal subregions
  (memory, learning)

Leranth, PNAS, 2008
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CERHRNatl Toxicology Program

• The NTP has some concern for effects on the
  brain, behavior, and prostate gland in fetuses,
  infants, and children at current human exposures
  to bisphenol A.

CERHR, Natl Toxicology Program, 2008
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Conclusion

• Multiple lines of evidence show that BPA is
  causally associated with and correlates with a
  number of health effects of concern to humans at
  current exposure levels
• Virtually the ENTIRE human population is exposed
• From a public health perspective, this means that
  the entire population is at risk
• Even if the additional risk from BPA is small
  for any given endpoint, the public health
  implications are highly significant

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Taking action

• Goal Protect public health primary prevention
• Choose between false positive vs. false negative
  errors (who decides?)
• Locate the burden of proof in the system
• Seek and implement safer alternatives
• Reduce uncertainties by pre-market safety
  testing of chemicals and materials e.g REACH
  in the EU