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Environmental Hormones and Gender Christine Johnson April 5, 2008.

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1 Environmental Hormones and Gender Christine Johnson April 5, 2008

2 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

3 Glands of the Endocrine System Source: Purves, et. al., 2003

4 Hypothalamic-Pituitary-Gonadal Axis System Model

5 Hormone Synthesis Pathways Source: White and Speiser, 2000

6 Developmental Timeline Source: Wilson, et. al., 1981

7 Mechanisms of Endocrine Disruption Source: McLachlan, 2001

8 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)

9 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

10 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)

11 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 Male9.5 2 Bisexual Male3.1 9 Transgender14.3 23 Transsexual (pre- or post-op)36.5 2 Intersex3.1 6 Androgynous9.5 1 Female1.5 1 Eunuch1.5 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

12 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.

13 Atrazine Usage in U.S. Source: Hayes et. al., 2003

14 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

15 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

16 DEHP Non-Linear Dose-response Curve Source: Andrade et. al., 2006

17 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

18 Phthalates Reduce Anogenital Distance in Baby Boys Source: Swan et. al., 2005

19 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

20 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

21 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

22 Estrogenic Potency Comparison Based on Inhibition of Estrogen Binding Inhibition of [ 3 H]17ß- estradiol binding to the estrogen receptor using in- vitro assay o,p'-DDT and nonylphenol caused a dramatic decrease in [ 3 H]17ß-estradiol binding: 60 and 75%, respectively. Source: Danzo (1997)

23 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

24 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

25 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

26 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

27 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

28 Non-Monotonic Dose-Response Curves Source: Welshons et. al. (2003)

29 Dose-Response Curve of Breast Cancer Cells Source: Welshons et. al. (2003)

30 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

31 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

32 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

33 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): Non- monotonic 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 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.

34 Ecojustice Canada (2008). Aamjiwnaang test finds high levels of hazardous chemicals. 2008. Accessed March 29, 2008 from: http://www.ecojustice.ca/media-centre/press-clips/localized-study-is-complete- aamjiwnaang-test-finds-high-levels-of-hazardous-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.gov/eims/eimscomm.getfile?p_download_id=36841 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.

35 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/farabee/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.

36 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 Hormonal Control of Sexual Development." Science 211(4488): 1278-1284.

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