What do Walleye, Wall-E, and Wall Street all have in ...

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has dubbed “Adam's rib” – a one-carbon unit. Estrogens influence human growth and development in utero for both males and females. Estrogens are the ...

Op-ed

What do Walleye, Wall-E, and Wall Street all have in common? The answer is not as obvious as one might think… As I’ve noted elsewhere, Dr. Oliver Wendell Holmes (1809-1894) reportedly said that if all of the medicines of his day could be “sunk to the bottom of the sea, it would be all the better for mankind – and all the worse for the fishes.”1 The quip was Holmes’s way of warning that people were becoming far too preoccupied with drugs, pills, and other “quick fix” prescriptions for greater comfort and better health. (Note that these two terms are not always synonymous). Today, as biologists investigate ominous reproductive disorders and other anomalies in growing numbers of aquatic organisms, Holmes’s remark appears almost prophetic. Consider, for example research described in the popular scientific publication Nature (2012 Nov 16): In a story titled “Human drugs make fish flounder,” Richard A. Lovett notes, “Scientists have known for years that human medications, from anti-inflammatories to the hormones in birth-control pills, are ending up in waterways and affecting fish and other organisms.”2 Among fathead minnows (Pimephales promelas), for example, exposure to the natural estrogen 17-βestradiol has been associated with outcomes ranging from impaired reproduction to reduced ability to elude predators. Eight years after government officials in the United Kingdom declared that the common synthetic estrogen ethinyl estradiol “feminizes” male fish and is contributing to reduced fish populations, the evidence against ethinyl estradiol “continues to mount” (Nature, 21 Nov 2012). As Natasha Gilbert reported, “In one of the largest studies of the problem, the UK government’s Environment Agency found in 2004 that 86% of male fish samples at 51 sites around the country were intersex.” (Nature, 22 Nov 2012).3 In Europe and the United States and other developed nations, fish and other aquatic organisms may be exposed to a variety of hormonally active compounds and their metabolites or conjugates. In March 2015, researchers at the University of Missouri noted that certain environmental estrogens, notably bisphenol A (BPA) and ethinyl estradiol are “ubiquitous” in aquatic environments throughout the U.S. and many other countries.4 Indeed, Bhandari and colleagues (2015) found that exposure to environmentally relevant quantities of ethinyl estradiol – commonly contained in most oral contraceptive regimens – led to reduced fertility rates and increased embryo mortality in a model fish population. Moreover, adverse impacts on population health persisted in offspring three generations later. Here it may be useful to offer a brief hormone tutorial: Natural progesterone is what we might call the “parent hormone” from which both testosterone and estrogen are derived. Estrogen is made in sequence from testosterone, through the removal of what at least one endocrinologist has dubbed “Adam’s rib” – a one-carbon unit. Estrogens influence human growth and development in utero for both males and females. Estrogens are the primary sex hormone in women, whereas testosterone is more abundant and influential in men. Estradiol is the most active form of estrogen in the body, and various isomers may be synthesized.5 The synthetic

derivative ethinyl estradiol is orally bioactive, is more resistant to degradation, and is commonly used in combined oral contraceptive pills. How bad is the problem -- and why should we care? The 2012 articles in Nature were prompted by proposed legislation then before the European Commission to limit annual average concentrations of ethinyl estradiol in surface waters and to require the upgrade of some 1,360 wastewater treatment facilities at a cost that could exceed $41 billion U.S. dollars over the next decade. One finding that has alarmed many researchers and policy makers came from a Canadian study in which chronic exposure of fathead minnows to low concentrations of 17-α-ethinyl estradiol led to altered oogenesis (egg development) in females, intersex characteristics (e.g., vitellogenesis) in males, and near extinction of this species from the experimental test lake. As the authors noted, this species is a freshwater equivalent of the miner’s canary in the coal mine -- and the proverbial canary is proving sick.6 Birth control pills containing ethinyl estradiol and other synthetic estrogens are not the only source of endocrine disruption in fish and other aquatic wildlife, and scientific concern is not new. Over the past two decades, signs of endocrine disruption have included, for example, skewed sex hormone ratios in alligators exposed to chemicals from production agriculture (Guillette et al., 2000, 2007); demasculinization of fathead minnows and other freshwater fish exposed to cattle feedlot effluent (Orlando et al., 2004); altered serum sex steroid levels among walleye (Stizostedion vitreum) exposed to municipal sewage treatment plant effluent (Folmar & Denslow et al., 2001); increased risk behavior and mortality among three-spined stickleback (Gasterosteus aculeatus) and intersex characteristics and impaired gonadal development among pearl dace (Margariscus margarita) after chronic, low-level exposure to ethinyl estradiol (Bell AM, 2004; Palace & Wautier et al., 2006).7 The US Environmental Protection Agency lists a multitude of compounds as potential endocrine disruptors, and the public is likely most familiar with those few that receive wide media attention: polychlorinated biphenyls (PCBs), bisphenol A (BPA) and so forth. Nevertheless, ethinyl estradiol and similar synthetic estrogens are of particular concern because of both their relative potency and the sheer number of users of hormonal contraception worldwide. Relative potency, worldwide use In the literature, references to “relative estrogenic effect” typically refer to 17-β-estradiol as the baseline substance, with even the “potent” nonylphenol ethoxylates showing an estrogenic effect about 5 to 6 orders of magnitude lower than that of 17-β-estradiol (Hohenblum et al., 2004).8 Ethinyl estradiol and other synthetic estrogens are of grave concern because these compounds are lipophilic, bioaccumulative, and associated with additive or synergistic effects.9 Greim (2004) observed: Safe [1995] calculated the estrogenic and anti-estrogenic potencies of xenoestrogens that may be ingested daily relative to 17-β-estradiol. A woman who takes a birth control pill ingests approximately 17,000 equivalents per day and during postmenopausal estrogen therapy ingests 3,300 equivalents, whereas

ingestion of estrogenic flavonids in food is 102 [equivalents] and of environmental organochlorine estrogens is 0.0000025.10 Consider these relative potencies in light of the sheer number of users of hormonal contraception worldwide: The number may be as high as 100 million women throughout the globe (there are an estimated 12–15 million current users in the United States alone), with 44.5 million American women ages 15–44 reported to have been “ever users” or one-time users of the oral contraceptive pill.11

Excretion and aquatic exposures Orally ingested ethinyl estradiol is metabolized in the liver; and well over half of any given dose (parent compound metabolites) is excreted in the urine and feces in a 4:6 ratio. Approximately 30% is excreted in the urine and bile as the glucuronide or sulphate conjugate.12 Thirty-six years ago, when 8.5 kg/day of salicylic acid, a metabolite of aspirin, was found in waste water effluent in Kansas City, it “prompted speculation” that with “millions of women taking oral contraceptives, some environmental contamination with estrogenic materials is a distinct possibility.”13 In 2011 Dr. Waldemar Grzybowski, a researcher with the Institute of Oceanography at the University of Gdansk, estimated that more than 50 percent and perhaps as high as 93 percent of the observed estrogenicity in European surface waters may be attributed to ethinyl estradiol.14 He arrived at this figure after checking original sources cited – and in numerous instances, misrepresented -- by authors funded through the Reproductive Health Technologies Project (USA) in the January 2011 issue of Environmental Science and Technology. The Reproductive Health Technologies Project is a self-described “advocacy organization” whose raison d'etre is to defend and promote the use of oral contraceptives and other birth control regimens worldwide.15 Dr. Gryzbowski’s painstaking rebuttal appeared just a few months later, in September 2011. Consider these errors exposed by Gryzbowski: A table claiming to show “total” daily estrogen excretion by human beings did not include total estrogens since the authors did not include ethinyl estradiol. Moreover, the authors supported by the Reproductive Health Technologies Project had described the sulfate conjugates of ethinyl estradiol as biologically “inactive,” when, in fact, such conjugates are readily hydrolyzed back to their active, estrogenic forms.16 Grzybowski further noted: “The authors are right that potency of the estrogens should be taken into account. The problem is that their estimates of estrogen potency are not correct.” Assuming more correctly and yet still conservatively that the relative potency of ethinyl estradiol to E1 (estrone) is 20, Grzybowski then re-calculated “estrogen concentrations in source and drinking water” using median figures in Table 5 of the disputed article. Whereas the authors funded by the Reproductive Health Technologies Project claimed that the contribution of ethinyl estradiol to the estrogenicity of surface waters is “relatively small,” Gryzbowski’s calculations – based on more accurate relative potencies – found its contribution to be major.

He is not alone: In February 2013, scientists publishing in the journal Environmental Pollution note that the “presence of the synthetic estrogen 17α-ethinylestradiol (EE2) in the environment is of increasing concern due to the endocrine disruption of aquatic organisms. Incomplete removal from wastewater (WW) is one of the main sources of EE2 in aquatic ecosystems, thus improving processes like biological WW treatment/activated sludge (AS) is becoming significantly important.” (Larcher and Yargeau, 2012).17 Whereas these authors are investigating the efficacy of activated sludge with heterotrophic bacteria in improving EE2 removal, other researchers have been examining methods such as ozonation and membrane bioreactors with or without powdered activated carbon.18 Such efforts have taken on urgency in light of mounting evidence that excretion of hormonal contraceptives and their metabolites have immediate and long-term effects on our aquatic and human ecosystems.

Walleye, Wall-E, and Wall Street In Disney’s award winning film Wall-E, we meet a lonely male robot tending his little corner of a dirty and desolate, post-materialist, post-consumerist world. Did such environmental degradation happen overnight, or was this, perhaps, a society that failed to “mind its minnows” – a society that failed to cherish the only gateway to the Future that any civilization has: fertile fields and streams and a fertile populace? In the film, hope enters in the form of Eve, a lively female robot who receives from Wall-E and secures in her programmed “womb” a tiny tender green shoot that – joy! – proves that life is yet possible on earth. The plot is pure mystery and adventure thereafter, and by the end of the film, viewers get the message that life – real living – is not about comfort, consumption and possessing, more always more. Rather, life is about something – someone – more. There is deep irony in our present concerns over ethinyl estradiol and other synthetic reproductive hormones in the environment: While scientists worry about indirect exposure of aquatic organisms to known endocrine disruptors, each day millions of otherwise healthy women directly ingest or insert hormonal contraceptives precisely for their endocrine disrupting effects. Today, when infertility and other reproductive disorders are found in sentinel species such as fish and frogs, we view it as a sign of environmental degradation. But the same conditions – when deliberately chemically induced in the complex ecosystem of the human female body – are touted as “safe,” inconsequential, and even desirable.

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Teresa A. Donovan, MPH, is affiliated with the NIEHS-funded Center for Environmental Genetics at the University of Cincinnati. Institution listed for purposes of affiliation only; the opinions expressed herein belong solely to the author and do not reflect official views of the University of Cincinnati or its College of Medicine.

Citations 1. Farmer L., ed. (1955) Doctors’ Legacy: A Selection of Physicians’ Letters, 1721-1954. New York: Harper and Bros, 4-5. 2. Lovett RA. Human drugs make fish flounder. Nature. 2012 Nov 16;491(7424). [doi:10.1038/ nature.2012.11843]. No author(s) listed. Water Wars [Editorial]. Nature 2012 Nov 21;491(7425):496. doi:10.1038/491496a 3. Gilbert N. Drug-pollution law all washed up. Nature. 2012 Nov 22;491(7425):503-4. 4. Bhandari RK, vom Saal FS, Tillitt DE. Transgenerational effects from early developmental exposures to bisphenol A or 17α-ethinylestradiol in medaka, Oryzias latipes.Sci Rep. 2015 Mar 20;5:9303. doi: 10.1038/srep09303. PMID: 25790734. 5. Tulane University Environmental Signaling Network. eHormone: http://e.hormone.tulane.edu/ [accessed online 2013 Feb 5]. University of California-Davis, Extension Toxicology Network. ExtoxNet http://extoxnet.orst.edu/faqs/natural/estrogen.htm [2013 Feb 5]. Harvard Center for Clinical and Translational Science. Harvard Catalyst: http://connects.catalyst.harvard.edu/profiles/profile/concept/estradiol [accessed 2013 Feb 5]. 6. Vitellogenesis, or yolk deposition, refers to the early development of oocytes (eggs) in female organisms; the induction of vitellogenin in male sentinel species is a reliable indicator of endocrine disruption: Sumpter JP, Jobling S. Vitellogenesis as a biomarker for estrogenic contamination in the aquatic environment. Environ Health Perspect. 1995;103 (suppl 7):173-78. Kidd KA, Blanchfield PJ, Mills KH, Palace VP, Evans RE, Lazorchak JM, Flick RW. Collapse of a fish population after exposure to a synthetic estrogen. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8897-901. PMID:17517636. See also Palace VP, Wautier KG, Evans RE, Blanchfield PJ, Mills KH, Chalanchuk SM, et al. Biochemical and histopathological effects in pearl dace (Margariscus margarita) chronically exposed to a synthetic estrogen in a whole lake experiment. Environ Toxicol Chem. 2006 Apr;25(4):1114-25. PMID: 16629151. 7. Guillette LJ Jr, Edwards TM, Moore BC. Alligators, contaminants and steroid hormones. Environ Sci. 2007;14(6):331-47. PMID:18030287. Guillette LJ, Crain DA, Gunderson M, Kools S, et al. Alligators and endocrine disrupting contaminants: A current perspective. American Zoologist. 2000;40:438-52. Guillette LJ, Crain DA, eds. Endocrine Disrupting Contaminants: An Evolutionary Perspective. Philadelphia, PA: Taylor and Francis, 2000. Orlando EF, Kolok AS, Binzcik GA, Gates JL, et al. (2004). Endocrine-disrupting effects of cattle feedlot effluent on an aquatic sentinel species, the fathead minnow. Environ Health Perspect. 2004;112(3). Accessed online at http://ehp.niehs.nih.gov/docs/2003/6591/abstract.html [2005 Apr 18]. Folmar LC, Denslow ND, Kroll K, Orlando EF, et al. Altered serum sex steroids and vitellogenin induction in walleye (Stizostedion vitreum) collected near a metropolitan sewage treatment plant. Archives Environ Contam Toxicol. 2001;40(3):392-98. Bell AM. An endocrine disruptor increases growth and risky behavior in three-spined stickleback (Gasterosteus aculeatus). Hormones and Behavior. 2004;45:108-14. Palace VP, Wautier KG, Evans RE, Blanchfield PJ, Mills KH, Chalanchuk SM, et al. Biochemical and histopathological effects in pearl dace (Margariscus

margarita) chronically exposed to a synthetic estrogen in a whole lake experiment. Environ Toxicol Chem. 2006 Apr;25(4):1114-25.PMID: 16629151. 8. Hohenblum P, Gans O, Moche W, Scharf S, Lorbeer G. Monitoring of selected estrogenic hormones and industrial chemicals in groundwaters and surface waters in Austria. Sci Total Environ. 2004;333:186-87 9. Sumpter JP, Jobling S. Vitellogenesis as a biomarker for estrogenic contamination in the aquatic environment. Environ Health Perspect. 1995;103 (suppl 7):173-78. Kolpin DW, Furlong ET, Meyer MT, Thurman EM., et al. Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999-2000: A national reconnaissance. Environ Sci Technol. 2002;36(6):1208, 1210. 10. Greim HA. The endocrine and reproductive system: Adverse effects of hormonally active substances. Pediatrics. 2004;113(4):1070-72. Citing Safe SH. Environmental and dietary estrogens and human health: Is there a problem? Environ Health Perspect. 1995;103:346-51. 11. Susheela Singh, et al., “Adding It Up: The Benefits of Investigating in Sexual and Reproductive Health Care” (New York: Alan Guttmacher Institute, 2003), 20. Alan Guttmacher Institute. (2005). Contraceptive Method Choice among U.S. Women Who Practice Contraception, 2002. Contraceptive Use. Accessed online at http://www.agiusa.org/pubs/fb_contr_use.pdf [2005 Jul 19]. See also Farrington A. (2002). Health and Sexuality: U.S. Women First in Line for Contraceptive Patch. Accessed online at http://www.arhp.org/healthcareproviders/onlinepublications/healthandsexuality.cfm [2005 Jul 19]. United States Centers for Disease Control and Prevention. National Center for Health Statistics. Advance Data. (2004). Use of Contraception and Use of Family Planning Services in the United States: 1982-2002. No. 350, 2004 Dec 10. Accessed online at http://www.cdc.gov/ nchs/data/ad/ad350.pdf [2013 Feb 4]. Guttmacher Institute. (2012 July). Fact Sheet: Contraceptive use in the United States. Accessed online at http://www.guttmacher.org/ pubs/fb_contr_use.html [2013 Feb 4]. 12. UCB Pharma Limited. Material data sheet: Ethinylestradiol Tablets BP 10 mcg, 50 mcg, 1 mg. http://www.medicines.org.uk/EMC/printfriendlydocument.aspx?documentid=16780 [accessed 2014 Feb 1]: “Hydroxylation appears to be the main metabolic pathway. 60% of a dose is excreted in the urine and 40% in the faeces. About 30% is excreted in the urine and bile as the glucuronide or sulphate conjugate.” NCBI PubChem 17 alpha ethinyl estradiol – Substance Summary: “In contrast to the metabolites of natural estrogen, a significant proportion of the metabolites of ethinylestradiol in humans are excreted by the fecal route; ethinylestradiol itself is excreted in urine and feces in a ratio of about 4:6. About 90% of the metabolites of tritiated ethinylestradiol are recovered in both feces and urine.” Accessed online at http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=56313453#x94 [2013 Feb 111]. According to Palace & Wautier, et al. 2006, fellow researchers (Kidd et al., unpublished data) determined the half-life of ethinylestradiol in an experimental test lake to be 12 days. 13. McLachlan J. A. (2001). Environmental signaling: What embryos and evolution teach us about endocrine disrupting chemicals. Endocrine Reviews 22 (3):326. Citing Hignite C. and

Azarnoff D. L. (1977). Drugs and drug metabolites as environmental contaminants: Chlorophenoxisobutyrate and salicylic acid in sewage water effluent. Life Science 20: 337-341; 14. Grzybowski W. Comment on "Are oral contraceptives a significant contributor to the estrogenicity of drinking water?" Environ Sci Technol. 2011 Sep 1;45(17):7605. PMID:21838254. Consider these errors exposed by Grzbowski: “Table 1, contrary to the author’s description, does not show ‘total estrogens’ since the authors did not include EE2. The daily dose of 10.5 μg, taken from ref 3 may be misleading regarding environmental impact of EE2. In my opinion, EE2-sulfate conjugates should not be regarded as ‘inactive EE2’. The only difference between glucoronide and sulfate conjugate is that the latter becomes active later. In addition, percentage of EE2 oxidation seems to be too high in the light of research on in vitro metabolism of EE2. The authors are right that potency of the estrogens should be taken into account. The problem is that their estimates of estrogen potency are not correct. Quote: ‘The potency of these estrogens are typically measured in relation to E2 (having a value of 1) and are estimated to have the following relative potencies: EE2: 2.0; E2: 1; E1: 0.20.4; E3: 0.024–0.026’. This statement is supposedly supported by refs 6, 12, 48, 49. I have checked these references and the results are as follows:    

Ref 6 contains no original data on the potency of estrogens; quote: ‘The relative efficiency of the estrogens to induce vitellogenesis is EE2 > E2 > E1, but the exact relationship is difficult to estimate’. Ref 12 contains no data on the potency of estrogens. Ref 48 quote: ‘Ethynylestradiol-17alfa was consistently the most potent steroid tested, with an estrogenic potency between 11 and 27 times greater than that of E2 and between 33 and 66 times greater than that of E1’. Ref 49 quote: ‘it is clear that EE2 is a very potent inducer of VTG with a relative potency of about 30 times higher than E2’.

One can estimate contribution of EE2 to total estrogenicity using Dutch population statistics and data on estrogens excretion presented in the paper. Assuming that the relative potency of EE2 is 20, its share in the total estrogenicity exceeds 50%. I finish my comment attempting to answer the title question ‘Are Oral Contraceptives a Significant Contributor to the Estrogenicity of Drinking Water?’. To do so, I used Table 5 medians and assumed that relative potency of EE2 is 20. The calculation suggests that oral contraceptives are responsible for 93% of estrogenicity in German drinking water. END Gryzbowski excerpts. 15. Wise A, O'Brien K, Woodruff T. Are oral contraceptives a significant contributor to the estrogenicity of drinking water? Environ Sci Technol. 2011 Jan 1;45(1):51-60. The authors acknowledge internship funding from the Reproductive Health Technologies Project, a selfdescribed contraceptive “advocacy” group: http://www.rhtp.org/about/default.asp [accessed 2013 Feb 5].

16. “Conjugates can reasonably be expected to be readily and rapidly hydrolyzed in the environment.” Colucci MS, Bork H, Topp E. Persistence of estrogenic hormones in agricultural soils: I. 17β-estradiol and estrone. J Environ Qual. 2001;30:2070. Citing, among others, Desbrow C, Routledge EJ, Brighty JP, et al. Identification of estrogenic chemicals in STW effluent: 1. Chemical fractionation and in vitro biological screening. Environ Sci Technol. 1998;32:15491558. “Metabolism following normal use frequently increases the polarity of metabolites— typically by conjugation—relative to the parent compound. The fact that such conjugation can be reversed by microbially mediated process during sewage treatment helps to account for observations of residues in the environment. Whilst the therapeutic effects are typically lowered or disappear following metabolism, some pharmacological or allergenic effects may be reactivated following deconjugation.” Webb S, Ternes T, Gibert M, Olejniczak K. Indirect human exposure to pharmaceuticals via drinking water. Toxicology Letters. 2003;142:165. PMID:12691710. 17. Larcher S, Yargeau V. Biodegradation of 17α-ethinylestradiol by heterotrophic bacteria. Environ Pollut. 2013 Feb;173:17-22. PMID:23195522 18. Yang W, Zhou H, Cicek N. Removal mechanisms of 17β-estradiol and 17α-ethinylestradiol in membrane bioreactors. Water Sci Technol. 2012;66(6):1263-9. PMID:22828304 19. Bhandari RK, vom Saal FS, Tillitt DE. op cit.

References in alphabetical order Bell A. M. (2004). An endocrine disruptor increases growth and risky behavior in three-spined stickleback (Gasterosteus aculeatus). Hormones and Behavior 45: 108-114. Bhandari RK, vom Saal FS, Tillitt DE. Transgenerational effects from early developmental exposures to bisphenol A or 17α-ethinylestradiol in medaka, Oryzias latipes.Sci Rep. 2015 Mar 20;5:9303. doi: 10.1038/srep09303. PMID: 25790734. Caldwell DJ, Mastrocco F, Hutchinson TH, Länge R, Heijerick D, Janssen C, Anderson PD, Sumpter JP. Derivation of an aquatic predicted no-effect concentration for the synthetic hormone, 17 alpha-ethinyl estradiol. Environ Sci Technol. 2008 Oct 1;42(19):7046-54. Colucci MS, Bork H, Topp E. Persistence of estrogenic hormones in agricultural soils: I. 17βestradiol and estrone. J Environ Qual. 2001;30:2070 Combalbert S, Hernandez-Raquet G. Occurrence, fate, and biodegradation of estrogens in sewage and manure. Appl Microbiol Biotechnol. 2010 May;86(6):1671-92.

Fick J, Lindberg RH, Parkkonen J, Arvidsson B, Tysklind M, Larsson DG. Therapeutic levels of levonorgestrel detected in blood plasma of fish: results from screening rainbow trout exposed to treated sewage effluents. Environ Sci Technol. 2010 Apr 1;44(7):2661-6. Folmar L. C., Denslow N. D., Kroll K., Orlando E. F., et al. (2001). Altered serum sex steroids and vitellogenin induction in walleye (Stizostedion vitreum) collected near a metropolitan sewage treatment plant. Archives of Environmental Contamination and Toxicology 40 (3): 392298. Gilbert N. Drug-pollution law all washed up. Nature. 2012 Nov 22;491(7425):503-4. Greim H. A. (2004). The endocrine and reproductive system: Adverse effects of hormonally active substances. Pediatrics 113 (4): 10701072. Grzybowski W. Comment on "Are oral contraceptives a significant contributor to the estrogenicity of drinking water?" Environ Sci Technol. 2011 Sep 1;45(17):7605. PMID:21838254. Guillette L. J., Crain D. A., Gunderson M., Kools S., et al. (2000). Alligators and endocrine disrupting contaminants: A current perspective. American Zoologist 40: 438-452. Guillette L. J. and Crain D. A., eds. (2000). Endocrine Disrupting Contaminants: An Evolutionary Perspective. Philadelphia, PA: Taylor and Francis. Guillette LJ Jr, Edwards TM, Moore BC. Alligators, contaminants and steroid hormones. Environ Sci. 2007;14(6):331-47. PMID:18030287. Guttmacher Institute. (2012 July). Fact Sheet: Contraceptive use in the United States. Accessed online at http://www.guttmacher.org/ pubs/fb_contr_use.html [3013 Feb 4]. Alan Guttmacher Institute. (2005). Contraceptive Method Choice among U.S. Women Who Practice Contraception, 2002. Contraceptive Use. Accessed online at http://www.agiusa.org/pubs/fb_contr_use.pdf [2005 Jul 19]. Hohenblum P., Gans O., Moche W., Scharf S., and Lorbeer G. (2004). Monitoring of selected estrogenic hormones and industrial chemicals in groundwaters and surface waters in Austria. Science of the Total Environment 333:186-187 Kidd KA, Blanchfield PJ, Mills KH, Palace VP, Evans RE, Lazorchak JM, Flick RW. Collapse of a fish population after exposure to a synthetic estrogen. Proc Natl Acad Sci U S A. 2007 May 22;104(21):8897-901. PMID:17517636. Kolpin D. W., Furlong E. T., Meyer M. T., Thurman E. M., et al. (2002). Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999-2000: A national reconnaissance. Environmental Science and Technology 36 (6): 1208, 1210. Larcher S, Yargeau V. Biodegradation of 17α-ethinylestradiol by heterotrophic bacteria.

Environ Pollut. 2013 Feb;173:17-22. PMID:23195522 Lovett RA. Human drugs make fish flounder. Nature. 2012 Nov 16;491(7424). [doi:10.1038/ nature.2012.11843]. Moschet C. Microbial degradation of steroid hormones in the environment and technical systems. Thesis, Swiss Federal Institute of Technology, Institute of Biogeochemistry and Pollutant Dynamics (IBP-ETH). Zurich. 2009 April. Accessed online at http://www.ibp.ethz.ch/research/aquaticchemistry/teaching/archive_past_lectures/term_paper_08 _09/HS08_CHRISTOPH_MOSCHET_rev_termpaper.pdf [2012 March 21]. I am grateful to Dr. Waldemar Grzybowski of the University of Gdansk, Institute for Oceanography, for calling this paper to my attention – td. Newbold RR. Developmental exposure to endocrine-disrupting chemicals programs for reproductive tract alterations and obesity later in life. Am J Clin Nutr. 2011 Dec;94(6 Suppl):1939S-1942S. PMID:22089436 Orlando E. F., Kolok A. S., Binzcik G. A., Gates J. L., et al. (2004). Endocrine-disrupting effects of cattle feedlot effluent on an aquatic sentinel species, the fathead minnow. Environmental Health Perspectives 112 (3). Palace VP, Wautier KG, Evans RE, Blanchfield PJ, Mills KH, Chalanchuk SM, et al. Biochemical and histopathological effects in pearl dace (Margariscus margarita) chronically exposed to a synthetic estrogen in a whole lake experiment. Environ Toxicol Chem. 2006 Apr;25(4):1114-25. PMID: 16629151. Safe S. H. (1995). Environmental and dietary estrogens and human health: Is there a problem? Environmental Health Perspectives 103:346-351. Singh S et al., “Adding It Up: The Benefits of Investigating in Sexual and Reproductive Health Care” (New York: Alan Guttmacher Institute, 2003), 20. Sumpter J.P. and Jobling S. (1995). Vitellogenesis as a biomarker for estrogenic contamination in the aquatic environment. Environmental Health Perspectives 103 (suppl 7): 173-78. Vidaeff A. C. And Sever L. E. (2005). In utero exposure to environmental estrogens and male reproductive health: A systematic review of biological and epidemiologic evidence. Reproductive Toxicology 20:11. Webb S, Ternes T, Gibert M, Olejniczak K. Indirect human exposure to pharmaceuticals via drinking water. Toxicology Letters. 2003;142:165. PMID:12691710. Wise A, O'Brien K, Woodruff T. Are oral contraceptives a significant contributor to the estrogenicity of drinking water?" Environ Sci Technol. 2011 Jan 1;45(1):51-60.

Yang W, Zhou H, Cicek N. Removal mechanisms of 17β-estradiol and 17α-ethinylestradiol in membrane bioreactors. Water Sci Technol. 2012;66(6):1263-9. PMID:22828304

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