Environmental Hormones and Gender. Christine Johnson April 5, 2008. Endocrine Disrupting Chemicals (EDC). EPA Definition:
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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
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 • 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 • 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)
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) ResponsesIssue/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
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.
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] • 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 • 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 • “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 • Inhibition of [3H]17ß-estradiol binding to the estrogen receptor using in-vitro assay • o,p'-DDT and nonylphenol caused a dramatic decrease in [3H]17ß-estradiol binding: 60 and 75%, respectively. Source: Danzo (1997)
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
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
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 Sex Ratio Skew
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 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
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 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
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
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