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Title: Questions


1
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?

2
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…

3
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

4
How hormones work
  • Bind to and activate specific receptors
  • those receptors then initiate a cascade of
    physiochemical events
  • hormone-receptor complex can act directly on DNA
    to generate gene products (enzymes, etc.) or can
    alter the activity of existing proteins

5
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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7
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.

8
Environmental estrogens
  • Sources
  • pesticides
  • plastics
  • pharmaceuticals
  • some cleansers
  • vs. phytoestrogens
  • antiherbivore compounds in many plant species
  • lignans (many fruits, vegetables), isoflavones
    (soy)

9
World Pesticide Use (FAO)
  • North America 40
  • Europe, Middle East, Africa 25
  • Asia Pacific 18
  • Latin America 17

10
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.
11
U.S. Agriculture Pesticide Use (106 lbs active
ingredients)
Gianessi and Marcelli. 1997. Pesticide Use in
U.S. Crop Production 1997 National Summary
Report
12
Some Hormonally Active Agents (NRC 2000)
  • PCBs
  • DDT and derivatives
  • Bisphenol A
  • Atrazine

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14
Fates of organic species
  • Transport
  • Degradation due to
  • hydrolysis (needs water)
  • photodegradation (needs uv light)
  • biodegradation (micro organisms)

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16
Persistence and Bioaccumulation
  • slow degradation --gt persistence
  • solubility in lipids (fats) generally results in
    bioaccumulation (increased concentration as you
    move up the food chain)

17
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

18
Brief history of PCBs Polychlorinated 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

19
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.

20
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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22
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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25
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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27
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?

28
Endocrine Disruptors and Wildlife
29
Wildlife Population Declines
  • male feminization
  • reduced male and female fertility
  • modified immune system
  • altered reproductive behavior
  • cancers of reproductive tract

30
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

31
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)

32
2M, located between two males fetuses 1M,
located next to one male fetus 0M, located next
to female fetuses
33
Laboratory studies (cont)
  • Some chemical have been shown to interact
    synergistically
  • organizational effects in fetal development gtgt
    activational effects in adults

34
Potential risks to humans
  • Testicular cancer
  • Prostate cancer
  • Sperm counts
  • Behavior
  • in utero exposure in primates gt hyperactivity and
    learning disorders in juvenilles

35
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
36
Competing explanations
  • Anthropogenic environmental estrogens
  • Phytoestrogens
  • Other environmental stresses
  • All of the above interacting in complex ways

37
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.

38
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

39
Uncertainty (cont)
  • Generational delay in many effects
  • non-monotonic dose responses

40
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


41
Policy Responses
  • Domestic
  • Better screening (EDSTAC gt ED Standardization and
    Validation Task Force)
  • NRC Synthesis
  • Research
  • Monitoring
  • Risk Analysis


42
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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45
Corporate Responses to Persistent Organic
Pollutants
  • Legal risk analysis (rational polluter)
  • Economic risk analysis (current profits vs future
    costs)
  • Exposure reduction

46
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

47
http//www.hclrss.demon.co.uk/class_pesticides.htm
l
48
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

49
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
50
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
51
Environmental Risks
  • Accelerated pest resistance
  • Non-target species
  • Outcrossing to wild species
  • Outcrossing to other crops

Creeping bentgrass
52
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

53
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, MPH Greater Boston Physicians
for Social Responsibility
54
Science to inform policy Hazard Assessment
  • Compound isolation and identification
  • Physical and chemical properties
  • Compound toxicity?
  • Persistence?
  • Ability to bioaccumulate?
  • Other ecological effects?

55
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
56
Components of Risk Analysis
  • Risk assessment
  • Source, exposure, effects
  • Comparative risk assessment
  • Risk communication
  • Risk management
  • Acceptable levels, control and reduction
    approaches, implementation, evaluation

57
Risk Characterization
  • Magnitude of effect vs. uncertainty
  • Cumulative effects

58
Concluding thoughts
59
Can Science Resolve the ED Issue?
  • Scientific method
  • Scientific Uncertainty
  • Burden of Proof

60
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

61
Sources of uncertainty
  • Semantic uncertainty
  • Measurement error
  • precision vs. accuracy
  • Inadequate sample size
  • Incorrect model
  • Incomplete model (Indeterminacy)

62
Sources of uncertainty (2)
  • Contingency
  • Complexity
  • Causality vs. correlation

63
Elements of strong science
  • Multiple working hypotheses
  • Logic
  • Exclusionary experiments
  • Good study design
  • Replication and controls
  • Explicit assumptions
  • Semantic clarity

64
Communicating Scientific Uncertainty
  • Uncertainty among scientists
  • Motivates work
  • Establishes objectivity
  • Public Science
  • Popularization
  • Translation
  • Spin
  • Controversy
  • Consensus
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