Questions

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Questions

• What is an endocrine disruptor?
• Where do EDs originate and how are they
  transported and transformed?
• Are they a significant threat to wildlife?
• Are they a significant threat to humans?
• How do we evaluate the risk?
• Are government and industry doing enough in
  addressing the issue and mitigating these threats?

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What is an endocrine disruptor?

• Substance that possesses properties that might be
  expected to lead to endocrine disruption in an
  intact organism
• Substance or mixture of substances that alters
  the structure or function(s) of the endocrine
  systems and causes adverse effects at the level
  of organisms, its progeny, populations or
  subpopulations of organisms

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The endocrine system

• Produces hormones that circulate through the body
  to control, regulate, and maintain normal
  physiological functions, reproduction,
  development, and behavior
• consists of glands, hormones, target cells

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How hormones work

• Bind to and activate specific receptors
• those receptors then initiate a cascade of
  physiochemical events
• hormone-receptor complex can act directlyon DNA
  to generate gene products (enzymes, etc.) or can
  alter the activity of existing proteins

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Hormone disruptors

• Interfere with the hormone synthesis, storage,
  release secretion, transport, elimination,
  binding, or
• temporarily or permanently alter feedback loops
  involving the brain, pituitary, gonads, thyroid
  gland, or other organs.

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Estrogens (e.g., estradiol)

• materials that stimulate tissue growth by
• promoting cell proliferation (DNA synthesis and
  cell division) in female sex organs (breasts,
  uterus),
• promoting hypertrophy, or increasing a cell's
  size, such as occurs in female breast and male
  muscle during puberty
• and initiating synthesis (making) of specific
  proteins.

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Environmental estrogens

• Sources
• pesticides
• plastics
• pharmaceuticals
• some cleansers
• vs. phytoestrogens
• antiherbivore compounds in many plant species
• lignans (many fruits, vegetables), isoflavones
  (soy)

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World Pesticide Use (FAO)

• North America 40
• Europe, Middle East, Africa 25
• Asia Pacific 18
• Latin America 17

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Figure 1. (A) Trends in annual rates of
application of nitrogenous fertilizer (N)
expressed as mass of N, and of phosphate
fertilizer (P) expressed as mass of P2O5, for all
nations of the world except the former USSR (18,
19), and trends in global total area of irrigated
crop land (H2O) (18). (B) Trends in global total
area of land in pasture or crops (18). (C) Trend
in global pesticide production rates, measured as
millions of metric tons per year (30). (D) Trend
in expenditures on pesticide imports (18) summed
across all nations of the world, transformed to
constant 1996 U.S. dollars. All trends are as
dependent on global population and GDP as on time
(Table 1). Tilman et al. Science April 2001.
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U.S. Agriculture Pesticide Use (106 lbs active
ingredients)
Gianessi and Marcelli. 1997. Pesticide Use in
U.S. Crop Production 1997National Summary
Report
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Some Hormonally Active Agents (NRC 2000)

• PCBs
• DDT and derivatives
• Bisphenol A
• Atrazine

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Fates of organic species

• Transport
• Degradation due to
• hydrolysis (needs water)
• photodegradation (needs uv light)
• biodegradation (micro organisms)

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Persistence and Bioaccumulation

• slow degradation --gt persistence
• solubility in lipids (fats) generally results in
  bioaccumulation (increased concentration as you
  move up the food chain)

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Bioaccumulation

• E.g., PCB in Great lake food web
• 1x in water column
• 250x in phytoplankton
• 500x in zooplankton
• 45,000x in mysid shrimp
• 835,000x in smelt
• 2,800,000x in Lake Trout
• 25,000,000x in Herring gull

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Brief history of PCBsPolychlorinated Biphenyls
(Francis, 1994)

• 210 isomers are PCBs
• Developed 1930s as high boiling point, stable
  heat transfer fluids
• 50 capicators and transformers, 20
  plasticizers, also used in hydraulic fluids,
  inks, lubricants, waxes, cutting oils, adhesives
• peak production in 1970 in US

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How much PCB was produced?

• 1930-1970 in US 1 billion lbs cumulative
  produced.
• peak year 85 million lbs/year produced in 1970.
• in world 200 million lbs/year in 1970.
• US after 1970 only in closed systems, after 1977
  stopped totally.
• Names Aroclor, Phenoclor, Fenclor, ...
• Major Producer Monsanto, Inc.

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PCBs released

• In the US in 1970 estimated 55 million lbs/year
  lost to environment.
• 80 to atmosphere through burning of paper,
  plastic or pain.
• 20 to surface water due to leaks, disposal of
  industrial wastes, leaching and atmospheric
  fallout.
• still PCBs left in transistors, etc.

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Fate of PCBs?

• Different PCBs decompose at different rates
• Most chlorinated are generally most toxic and
  decompose slowest
• generally very persistent, highly soluble in fat,
  not very soluble in water

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PCB Concentration in Animals?

• Fish in Lake Michigan 10-15 ppm.
• Shark Liver 218 ppm.
• Brown pelican fat 266 ppm.
• Bioaccumulation in Lake Superior from water to
  fish was 1 million fold.
• Humans 1-2 ppm. Milk .5 ppm.

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Future?

• Still much PCBs remaining in environment.
• Can clean up closed sources.
• Contaminated soils or water is too expensive and
  contains risk--where do you put soils?

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Endocrine Disruptors and Wildlife
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Wildlife Population Declines

• male feminization
• reduced male and female fertility
• modified immune system
• altered reproductive behavior
• cancers of reproductive tract

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Some Wildlife Observations

• Female fish downstream from pulp mills have
  developed male organs and have altered behavior
• nearly all birds and fish in the Great Lakes have
  abnormal thyroids (low iodine?)
• Wadden Sea seals have lowered reproductive
  success associated with DDT/DDE
• male feminization and reproductive failure of
  alligators in Lake Apopka, FL associated with
  DDT/DDE

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Laboratory studies

• Most effects at low exposure levels (ppb) in
  offspring of adult females exposed during
  pregancy
• Non-linear (often modal) dose responses of
  experimental mammals
• Extreme time sensitivity of effect (e.g., male
  mice exhibit abnormalities if mother exposed to
  small quantities of dioxin during day 15 of
  pregnancy)

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2M, located between two males fetuses 1M,
located next to one male fetus 0M, located next
to female fetuses
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Laboratory studies (cont)

• Some chemical have been shown to interact
  synergistically
• organizational effects in fetal development gtgt
  activational effects in adults

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Potential risks to humans

• Testicular cancer
• Prostate cancer
• Sperm counts
• Behavior
• in utero exposure in primates gt hyperactivity and
  learning disorders in juvenilles

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Swan, Shanna H. and Eric P. Elkin. 1999.
Declining semen quality Can the past inform the
present? BioEssays, 21614-621. Shanna H. Swan,
Eric P. Elkin, and Laura Fenster. 1997. Have
Sperm Densities Declined? A Reanalysis of Global
Trend Data. Evironmental Health Perspect
1051228-1232 (1997).
Several studies during the past 20 years have
suggested a decline in sperm count or density.
The most controversial of these
analyses, published in 1992 (Carlsen et al.)
found a 50 decline in sperm density between 1938
and 1990. A flood of criticism followed this
analysis of 61 studies. By eliminating the major
criticisms of these studies, these new findings
add support for the conclusion that significant
declines in average sperm concentrations have
taken place in Europe and the United States since
the 1940s. Vs. Updates from Steve Safe
Several studies during the past 20 years have
suggested a decline in sperm count or density.
The most controversial of these
analyses, published in 1992 (Carlsen et al.)
found a 50 decline in sperm density between 1938
and 1990. A flood of criticism followed this
analysis of 61 studies. By eliminating the major
criticisms of these studies, these new findings
add support for the conclusion that significant
declines in average sperm concentrations have
taken place in Europe and the United States since
the 1940s. Vs. Updates from Steve Safe
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Competing explanations

• Anthropogenic environmental estrogens
• Phytoestrogens
• Other environmental stresses
• All of the above interacting in complex ways

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Conflicting Reports Some Examples

• Bisphenol A
• Per our Stolen Future
• Per American Plastics Council
• Atrazine
• Hayes et al. Nature
• Industry response to Hayes et al.

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Sources of uncertainty

• Biological complexity of endocrine system
• interactions with neurological and immune systems
• interactions with genetic and environmental
  factors
• species-specific susceptibility
• biological response to multiple, time-dependent
  exposures to multiple compounds

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Uncertainty (cont)

• Generational delay in many effects
• non-monotonic dose responses

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Policy Responses

• International
• Stockholme Convention on Persistent Organic
  Pollutants
• Use of many pesticides and plasticizers now
  highly restricted in many European countries.
• EU ban on atrazine

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Policy Responses

• Domestic
• Better screening (EDSTAC gt ED Standardization and
  Validation Task Force)
• NRC Synthesis
• Research
• Monitoring
• Risk Analysis

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Pesticides of concern some examples

• Chlordane (banned)
• Mirex (banned)
• Toxaphene (restricted)
• Lindane (restricted)
• Alachlor (active)
• Vinclozolin (active)
• Glyphosphate (roundup) (active)

Database at http//www.pesticideinfo.org/Index.htm
l
Maps at http//ca.water.usgs.gov/pnsp/use92/index.
htmll
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Corporate Responses to Persistent Organic
Pollutants

• Legal risk analysis (rational polluter)
• Economic risk analysis (current profits vs future
  costs)
• Exposure reduction

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Corporate Responses to Persistent Organic
Pollutants

• Manage perception
• Precautionary research
• http//www.monsanto.com/monsanto/layout/sci_tech/c
  rop_chemicals/default.asp
• Precautionary product substitutes
• http//www.shareholder.com/mattel/news/19980923-54
  258.cfm
• Get a competitive jump (e.g. phase in
  alternatives, promote new markets)
• Interview with former CEO of Monsanto Robert
  Shapiro
• Green alternatives (e.g., green pesticides,
  plastics alternatives)
• http//www.epea.com/english/introduction.html

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http//www.hclrss.demon.co.uk/class_pesticides.htm
l
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Crop losses to agricultural pests

• Loss of 35 of global crop production (Pimentel
  1996)
• Insects 13
• Plant pathogens 12
• Weeds 10
• 67,000 known pest species

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Biotechnology Panacea or Pandoras Box?

• gt20 of global crop of soybeans, corn, cotton and
  canola is GMO
• Crop seed market 30B
• Corporate giants
• Monsanto
• Archer Daniels Midland
• Cargill Inc.
• Kraft Foods International
• Syngenta Ag Company
• Dow AgroSciences

European Corn Borer
http//www.monsanto.com/monsanto/layout/default_nf
.asp
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Potential Benefits of GMO crops

• Reduced pesticide applications
• Better targeting
• Reduced drift
• Worker safety
• Improved yields
• Use of marginal soils

http//www.ces.ncsu.edu/plymouth/graphics/ent/yiel
dgard03/photo2.jpg
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Environmental Risks

• Accelerated pest resistance
• Non-target species
• Outcrossing to wild species
• Outcrossing to other crops

Creeping bentgrass
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Some examples of Green Chemistry in Theory and
Practice

• Ionic Liquid Solvents
• Genacys
• Chemical re-use and re-cylcing
• Petretec  Duponts Technology for Polyester
  Regeneration
• Green pesticides
• Design Chemistry

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How precautionary should we be?
We are engaged in a large global experiment. It
involves widespread exposure of all species of
plants and animals in diverse ecosystems to
multiple manmade chemicals. And in flagrant
disregard of the notion of informed consent which
underlies medical experimentation and treatment,
those exposed are frequently uninformed and have
rarely given consent. Instead, the limits of
science and rigorous requirements for
establishing causal proof often conspire with a
perverse requirement for proving harm, rather
than safety, to shape public policies which fail
to ensure protection of public health and the
environment.
Ted Schettler MD, MPHGreater Boston Physicians
for Social Responsibility
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Science to inform policy Hazard Assessment

• Compound isolation and identification
• Physical and chemical properties
• Compound toxicity?
• Persistence?
• Ability to bioaccumulate?
• Other ecological effects?

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Risk assessment (Harwood 2000)

• Risk probability that something undesirable
  will happen due to a threatening or hazardous
  process
• Risk assessment perception and/or
  quantification of that probability in the context
  of social goals and public decision making.

http//risk.lsd.ornl.gov/CRE/rais_site_map.shtml
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Components of Risk Analysis

• Risk assessment
• Source, exposure, effects
• Comparative risk assessment
• Risk communication
• Risk management
• Acceptable levels, control and reduction
  approaches, implementation, evaluation

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Risk Characterization

• Magnitude of effect vs. uncertainty
• Cumulative effects

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Concluding thoughts
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Can Science Resolve the ED Issue?

• Scientific method
• Scientific Uncertainty
• Burden of Proof

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Scientific method

• Observe (measure, map, monitor)
• Form hypothesis
• Design a test of the hypothesis
• Conduct study
• Theory can never be proved true, just false
• Report findings to peers
• Replicate study

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Sources of uncertainty

• Semantic uncertainty
• Measurement error
• precision vs. accuracy
• Inadequate sample size
• Incorrect model
• Incomplete model (Indeterminacy)

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Sources of uncertainty (2)

• Contingency
• Complexity
• Causality vs. correlation

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Elements of strong science

• Multiple working hypotheses
• Logic
• Exclusionary experiments
• Good study design
• Replication and controls
• Explicit assumptions
• Semantic clarity

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Communicating Scientific Uncertainty

• Uncertainty among scientists
• Motivates work
• Establishes objectivity
• Public Science
• Popularization
• Translation
• Spin
• Controversy
• Consensus