Transcript Environmental Hormones and Gender

Environmental Hormones and Gender
Christine Johnson
April 5, 2008
Endocrine Disrupting Chemicals (EDC)
EPA Definition:
“An environmental endocrine or hormone disruptor may
be defined as 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.”
Source: EPA/630/R-96/012. Crisp, et. al., 1997
Glands of the Endocrine System
Source: Purves, et. al., 2003
Hypothalamic-Pituitary-Gonadal
Axis System Model
Hypothalamus
GnRH
Pituitary
Testosterone
Estrogen
LH
Ovaries
Testes
Hormone Synthesis Pathways
Source: White and Speiser, 2000
Developmental Timeline
Source: Wilson, et. al., 1981
Mechanisms of Endocrine Disruption
Source: McLachlan, 2001
Classes of EDCs
1)
2)
3)
4)
5)
6)
7)
8)
9)
Heavy Metals (Cadmium, Mercury, Lead, Arsenic)
Combustion by-products (PAHs)
Pharmaceuticals (DES, Birth control, Cancer drugs)
Pesticides (DDT, dieldrin, etc)
Plasticizers (DEHP, DBP, BBP)
Plastic monomers (Bisphenol-A)
Flame Retardants (PBDEs)
Detergents/surfactants (nonylphenol, octylphenol)
Persistent Organochlorines (PCBs, dioxins, furans)
Pharmaceuticals
• Diethylstilbestrol (DES) Pharmaceutical drug prescribed to 5-7% of
pregnant women from 1941 to 1971
• Birth Control Pills (Ethynylestradiol) Widely used to inhibit pregnancy
• Estrogen replacement therapy (Premarin, others)
• Cancer Treatment Drugs (Antineoplastics) Tamoxifen, other hormone
blockers
• Synthetic hormone agonists and antagonists
DES Effects in Humans
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Diethylstilbestrol (DES)
Pharmaceutical drug prescribed to 5-7% of pregnant
women from 1941 to 1971
Pulled from market due to 7 cases of rare vaginal clearcell adenocarcinoma in daughters
DES Sons’ International Network found high fraction of
DES sons had gender identity issues.
Multigenerational effects have been demonstrated
Study of gender changes not studied (claimed that TG
changes are ‘rare’ and would not be observed)
DES Sons’ International Network Survey
If you were talking with your closest friend who likes you "just as you are," what term
would you use to represent how you define yourself at the present time? (choose one)
Responses
11
6
2
9
23
2
6
1
1
2
Issue/Topic
Straight Male
Gay Male
Bisexual Male
Transgender
Transsexual (pre- or post-op)
Intersex
Androgynous
Female
Eunuch
Other
% of Respondents
17.5
9.5
3.1
14.3
36.5
3.1
9.5
1.5
1.5
3.1
TOTAL: 63 Individual Responses from 102 subscribers (Approximately 65-70% response
rate for an estimated 90-95 active list participants in January 2002)
Source: Kerlin and Beyer, 2002
Pesticides
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Earliest pesticides based on lead and arsenic (late 1800s to mid 1940s)
DDT introduced early 1940s in WWII
Widespread use of DDT, Aldrin, Dieldrin until early 1970s
DDT used in agriculture, public health programs, insect eradication
DDT banned by EPA in 1972 and replaced by more potent pesticides
Less data available for newer pesticides
Small number of pesticides currently under review by EDSTAC
Effect endpoints are undefined by EPA
Numerous pesticides are found in freshwater streams and lakes in U.S.
Atrazine Usage in U.S.
Source: Hayes et. al., 2003
Atrazine Induces Aromatase Enzyme
“Atrazine is a potent endocrine disruptor
that both chemically castrates and
feminizes male amphibians.
It also disrupts normal gonadal
development and feminizes the
gonads of developing males.”
Source: Hayes et. al., 2006
Plasticizers (Phthalates) [tha-lates]
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Additive used to soften hard, brittle plastics
DEHP, DBP, others
Common in many personal care products, cosmetics and fragrances
Used in manufacture of soft PVC (shower curtains, etc.)
Used in manufacture of food containers and wraps (Saran wrap, etc)
Completely unregulated
Disclosure on labeling not required
Found to be readily transported to food, particularly food high in fat
content and especially when heated
• Found in humans in high concentrations, on par with concentrations
known to cause adverse effects in laboratory animals
DEHP Non-Linear Dose-response Curve
Source: Andrade et. al., 2006
Phthalates and AGI
1)
2)
3)
4)
Anogenital index is a measure of distance from genitalia
to anus
Index is smaller among females
Exposure to phthalates reduces this distance in males
indicating feminization.
Effect size is related to level of exposure
Phthalates Reduce Anogenital Distance in Baby Boys
Source: Swan et. al., 2005
Bisphenol-A
• Monomer used in the production of plastics, polycarbonate
• Present in food can linings, dental sealants and composite dental filling
materials
• Binds with estrogen receptor gamma with equal efficiency as estradiol
• Present in many plastics used for food and water storage
• Low-dose effects recently identified
• Approved by FDA based on only two studies, one using flawed
techniques, and another never published.
• Found in humans in high concentrations, on par with concentrations
known to cause adverse effects in laboratory animals
Detergents, Surfactants
• Nonylphenol, Octylphenol, others
• Common constituent of industrial and heavy-duty cleaning products
• Used as additive for many agricultural products to improve surface
adhesion (surfactant)
• Completely unregulated: Nonylphenol is on EPAs 4-B inert list,
making it suitable for organic agriculture
• Labeling is not required
• This class of chemicals is commonly found in the U.S. population and
in streams
Nonylphenol Common in Foods
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•
“4-Nonylphenols (NPs) are
common products of
biodegradation of a widely
used group of nonionic
surfactants,the
nonylphenol ethoxylates
(NPEs).”
“These compounds are
known to be persistent,
toxic, and estrogen active.”
Source: Guenther et. al., 2002
Estrogenic Potency Comparison Based on Inhibition
of Estrogen Binding
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Inhibition of [3H]17ßestradiol binding to the
estrogen receptor using invitro assay
o,p'-DDT and nonylphenol
caused a dramatic decrease
in [3H]17ß-estradiol
binding: 60 and 75%,
respectively.
Source: Danzo (1997)
Persistent Organochlorines
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Polychlorinated Biphenyls (capacitors, transformers, etc)
Dioxins (Agent Orange; also by-product of burning plastics)
Furans (product of burning plastics)
Complex molecular shapes with varying degrees of endocrine
disrupting properties (congeners)
• Breakdown in environment is very slow
• Transport easily by global distillation towards polar regions
• Present virtually everywhere in environment
Other Concerns
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Inuit populations in Greenland and Canada found to have skewed
sex-ratios
Decrease in number of boys compared to girls
Infertility current affects 1 in 10 couples (Achermann and Jameson,
1999)
Majority of infertility cases are idiopathic (unknown cause)
Sperm counts have been declining for the last 50 years
Testicular cancer also increasing, mainly among young men
(Carlsen, et al, 1995)
Cause is suspected to be due to endocrine disrupting chemicals
Sex Ratio Skew
• Sex ratio skew in Sarnia,
Ontario (pop: ~900)
• First Nations Community
of Aamjiwnaang,
surrounded by
petrochemical facilities
• Community air sampling
has found numerous
known toxins and
suspected endocrine
disruptors (Ecojustice
Canada, 2008)
Source: Mackenzie, et. al., 2005
Generally Untested at Any Level
• In 1996, Our Stolen Future was published – A new ‘Silent Spring’
(Colborn, et. al., 1996)
• That same year, after Congressional hearings with endocrine disruptor
scientists, the EPA was charged by Congress with evaluating the
effects and relative risk of EDCs, EDSTAC was formed.
• As of 2008, no testing has been performed, and only a preliminary list
of 68 pesticides and 4 phthalates have been proposed for testing
• EPA panels are heavily stacked with industry representatives and
scientists
• Independent researchers report effects, while industry scientists find no
effects
• Basic premise of toxicology that ‘the dose makes the poison’ is invalid
for endocrine disruptors
Something from “Nothing”
• Adding individual chemicals
together, each at the NoObserved-Effects Level
(NOEL) resulted in a
significant effect.
• “Error bars indicate the upper
95% confidence limit of
responses. In view of the
good agreement between CA
prediction and experimental
observation (MIX) the
combined effect of all agents
may be called (concentration)
additive.”
Source: Rajapakse et. al., 2002
Non-Monotonic Dose-Response Curves
Source: Welshons et. al. (2003)
Dose-Response Curve of Breast Cancer Cells
Source: Welshons et. al. (2003)
Toxicity is the wrong paradigm
• Toxicology assumes that low-dose effects will be smaller than highdose effects
• This is the linear model of toxicological action
• Research in the last decade shows non-monotonic dose-response
curves (non-linear dose-response curves)
• Effects can be more significant at low dose than at high dose
• Therefore, high dose testing cannot be used to predict effects at low
doses.
• Consequently, all existing data is inadequate for determining safe
exposure levels
Regulatory difficulties
• Regulatory structure is predicated on evaluating risk for individual
chemicals
• Real-life exposures are multiple; multiple chemicals can exert similar,
or additive effects
• Effects are not strictly toxic, they do not necessarily result in death
• EDCs can redirect, alter, or modulate development
• Endpoints are difficult to discern, measure, and quantify
• Industry influence is pervasive in regulatory process
• EPA performs little testing, depends upon manufacturers for data
• Even High Production Volume (HPV) chemicals have little data
• Effects on one species can differ from effects in another
Conclusions
• Sex and gender can be altered by exposure to hormonally
active chemicals during development
• These chemicals are now widespread and integrated into
modern commerce and products
• Sex and gender effects have been “missed” by
toxicologists and regulators, placing virtually everyone at
risk, especially the developing fetus
• Recognition of sex and gender endpoints is vital
• A shift to the precautionary principle is necessary
References
Achermann, J. C. and J. L. Jameson (1999). "Fertility and Infertility: Genetic
Contributions from the Hypothalamic-Pituitary-Gonadal Axis." Mol Endocrinol
13(6): 812-818.
Andrade A.J.M., Grande S.W., et al. (2006). "A dose–response study following in
utero and lactational exposure to di-(2-ethylhexyl)-phthalate (DEHP): Nonmonotonic dose–response and low dose effects on rat brain aromatase activity."
Toxicology 227: 185-192.
Carlsen, E., A. Giwercman, et al. (1995). "Declining Semen Quality and Increasing
Incidence of Testicular Cancer: Is There a Common Cause?" Environmental
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Colborn, T., D. Dumanowski, et al. (1996). Our Stolen Future: Are We Threatening
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