Environmental Hormones and Gender

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Environmental Hormones and Gender

• Christine Johnson
• April 5, 2008

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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

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Glands of the Endocrine System
Source Purves, et. al., 2003
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Hypothalamic-Pituitary-Gonadal Axis System Model
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Hormone Synthesis Pathways
Source White and Speiser, 2000
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Developmental Timeline
Source Wilson, et. al., 1981
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Mechanisms of Endocrine Disruption
Source McLachlan, 2001
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Classes of EDCs

1. Heavy Metals (Cadmium, Mercury, Lead, Arsenic)
2. Combustion by-products (PAHs)
3. Pharmaceuticals (DES, Birth control, Cancer
   drugs)
4. Pesticides (DDT, dieldrin, etc)
5. Plasticizers (DEHP, DBP, BBP)
6. Plastic monomers (Bisphenol-A)
7. Flame Retardants (PBDEs)
8. Detergents/surfactants (nonylphenol, octylphenol)
9. Persistent Organochlorines (PCBs, dioxins, furans)

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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

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DES Effects in Humans

• 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
  clear-cell 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)

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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 Issue/Topic of
  Respondents
• 11 Straight Male 17.5
• 6 Gay Male 9.5
• 2 Bisexual Male 3.1
• 9 Transgender 14.3
  
• 23 Transsexual (pre- or post-op) 36.5
  
• 2 Intersex 3.1
• 6 Androgynous 9.5
• 1 Female 1.5
• 1 Eunuch 1.5
• 2 Other 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

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Pesticides

• 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.

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Atrazine Usage in U.S.

• Source Hayes et. al., 2003

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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

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Plasticizers (Phthalates) tha-lates

• 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

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DEHP Non-Linear Dose-response Curve

• Source Andrade et. al., 2006

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Phthalates and AGI

1. Anogenital index is a measure of distance from
   genitalia to anus
2. Index is smaller among females
3. Exposure to phthalates reduces this distance in
   males indicating feminization.
4. Effect size is related to level of exposure

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Phthalates Reduce Anogenital Distance in Baby Boys

• Source Swan et. al., 2005

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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

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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

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Nonylphenol Common in Foods

• 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

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Estrogenic Potency Comparison Based on Inhibition
of Estrogen Binding

• Inhibition of 3H17ß-estradiol binding to the
  estrogen receptor using in-vitro assay
• o,p'-DDT and nonylphenol caused a dramatic
  decrease in 3H17ß-estradiol binding 60 and
  75, respectively.
• Source Danzo (1997)

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Persistent Organochlorines

• 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

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Other Concerns

• 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

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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

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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

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Something from Nothing

• Adding individual chemicals together, each at the
  No-Observed-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

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Non-Monotonic Dose-Response Curves

• Source Welshons et. al. (2003)

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Dose-Response Curve of Breast Cancer Cells

• Source Welshons et. al. (2003)

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Toxicity is the wrong paradigm

• Toxicology assumes that low-dose effects will be
  smaller than high-dose 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

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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

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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

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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
  doseresponse study following in utero and
  lactational exposure to di-(2-ethylhexyl)-phthalat
  e (DEHP) Non-monotonic doseresponse 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 Health Perspectives 103(Suppl. 7)
  137-139.
• Colborn, T., D. Dumanowski, et al. (1996). Our
  Stolen Future Are We Threatening Our Fertility,
  Intelligence, and Survival? A Scientific
  Detective Story. New York, Plume. See also
  http//www.ourstolenfuture.org
• Danzo, B. J. (1997). "Environmental Xenobiotics
  May Disrupt Normal Endocrine Function by
  Interfering with the Binding of Physiological
  Ligands to Steroid Receptors and Binding
  Proteins." Environmental Health Perspectives
  105(3) 294-301.

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• Ecojustice Canada (2008). Aamjiwnaang test finds
  high levels of hazardous chemicals. 2008.
  Accessed March 29, 2008 from http//www.ecojustic
  e.ca/media-centre/press-clips/localized-study-is-c
  omplete-aamjiwnaang-test-finds-high-levels-of-haza
  rdous-chemicals/
•  
• EPA. Crisp T.M., Clegg E.D., et al. (1997).
  SPECIAL REPORT ON ENVIRONMENTAL ENDOCRINE
  DISRUPTION AN EFFECTS ASSESSMENT AND ANALYSIS.
  Washington, D.C., U.S. Environmental Protection
  Agency 1-111. Available at http//oaspub.epa.go
  v/eims/eimscomm.getfile?p_download_id36841
•  
• Guenther K., Heinke V., et al. (2002). "Endocrine
  Disrupting Nonylphenols Are Ubiquitous in Food."
  Environmental Science and Technology 36
  1676-1680.
• Hayes T.B., Kelly Haston, et al. (2003).
  "Atrazine-Induced Hermaphroditism at 0.1 ppb in
  American Leopard Frogs (Rana pipiens) Laboratory
  and Field Evidence." Environmental Health
  Perspectives 111(4) 568-575.
•  
• Hayes T.B., Stuart A.A., et al. (2006).
  "Characterization of Atrazine-Induced Gonadal
  Malformations in African Clawed Frogs (Xenopus
  laevis) and Comparisons with Effects of an
  Androgen Antagonist (Cyproterone Acetate) and
  Exogenous Estrogen (17â-Estradiol) Support for
  the Demasculinization/Feminization Hypothesis."
  Environmental Health Perspectives 114(suppl 1)
  134-141.

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• Kerlin S. and Beyer D. (2002). The DES Sons
  Online Discussion Network Critical Issues and
  the Need for Further Research. Personal
  correspondence, June 28, 2002.
• Mackenzie C.A., Lockridge A., et al. (2005).
  "Declining Sex Ratio in a First Nation
  Community." Environmental Health Perspectives
  113(10) 1295-1298.
• McLachlan, J. A. (2001). "Environmental
  Signaling What Embryos and Evolution Teach Us
  About Endocrine Disrupting Chemicals." Endocrine
  Reviews 22 319-341.
• Purves, W. K., G. H. Orians, et al. (1992). Life
  the science of biology, 4th Edition, Sinauer
  Associates. http//www.emc.maricopa.edu/faculty/fa
  rabee/BIOBK/BioBookENDOCR.html
• Rajapakse N., Silva E., et al. (2002). "Combining
  Xenoestrogens at Levels below Individual
  No-Observed-Effect Concentrations Dramatically
  Enhances Steroid Hormone Action." Environmental
  Health Perspectives 110 917-921.

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• Swan S.H., Main K.M., et al. (2005). "Decrease in
  Anogenital Distance among Male Infants with
  Prenatal Phthalate Exposure." Environmental
  Health Perspectives 113(8) 1056-1061.
• Welshons, W. V., K. A. Thayer, et al. (2003).
  "Large Effects from Small Exposures. I.
  Mechanisms for Endocrine-Disrupting Chemicals
  with Estrogenic Activity." Environmental Health
  Perspectives 111(8) 994-1006.
• White, P. C. and P. W. Speiser (2000).
  "Congenital Adrenal Hyperplasia due to
  21-Hydroxylase Deficiency." Endocrine Reviews
  21(3) 245-291.
• Wilson, J. D., F. W. George, et al. (1981). "The
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  211(4488) 1278-1284.

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