A Historical Perspective on Endocrine Disruption as an Emerging Multifaceted Medical Problem
Main Article Content
Abstract
This historical perspective outlines how advances in endocrinology are uncovering mechanisms by which environmental chemicals may interfere in the synthesis and actions of hormones. Such chemicals have been termed endocrine disrupting chemicals (EDCs). Advances in understanding of receptor-mediated genomic and non-genomic actions of hormones have demonstrated the ability of EDCs to compete with hormone for binding to receptors in target cells and thereby to either mimic or antagonise hormone action. Advances in development of a range of assays for identifying endocrine activity of environmental chemicals have led to an appreciation of the wide distribution of EDCs to which the human population are now exposed in air, water, food and consumer products. Technological advances for measuring EDC concentrations in human tissues have demonstrated their widespread presence in human urine, blood, milk, adipose tissue, placenta and breast. Advances in understanding of the wide-ranging physiological effects of hormones and underlying defects in endocrine disorders have begun to reveal how EDCs may provide a new dimension to endocrine dysfunction. Evidence is accumulating for a role of EDCs in many male and female reproductive disorders, thyroid and adrenal disorders, immune system dysfunction and metabolic disorders including obesity, diabetes and cardiovascular disease. Deregulation of hormonally controlled cell growth may contribute to development of endocrine cancers. Adverse effects of EDCs on developmental processes, including neurodevelopment, have implications for child health and for appearance of disorders not only in later adult life but also into future generations.
Keywords:
Endocrine disruption, endocrine-disrupting chemicals, endocrine disrupters
Article Details
How to Cite
DARBRE, Philippa D..
A Historical Perspective on Endocrine Disruption as an Emerging Multifaceted Medical Problem.
Medical Research Archives, [S.l.], v. 9, n. 9, sep. 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2529>. Date accessed: 24 dec. 2024.
doi: https://doi.org/10.18103/mra.v9i9.2529.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. World Health Organisation, International Labour Organisation, and United Nations Environment Programme. Global assessment of the state-of-the-science of endocrine disruptors, (editors T. Damstra, S. Barlow, A. Bergman, R. Kavlok, G. VanderKraak) (WHO/PCS/EDC/02.2) (2002) Available at: https://www.who.int/ipcs/publications/new_issues/endocrine_disruptors/en/ [accessed 04 May 2021].
2. Darbre PDD (editor). Endocrine Disruption and Human Health, Elsevier, 2015 (second edition pending autumn 2021).
3. McNutt SH, Purwin P, Murray C. Vulvo-vaginitis in swine: preliminary report. J Am Vet Med Assoc. 1928; 73: 484.
4. Bennets H, Underwood EJ, Shier FL. A specific breeding problem of sheep on subterranean clover pasture in Western Australia. Aust Vet J. 1946; 22: 2-12.
5. Bennett JW, Klich M. Mycotoxins. Clin Microbiol Rev. 2003; 16: 497-516.
6. Woods, H.F. (chairman), Phytoestrogens and health. Crown copyright UK, 2003.
7. Burlington H, Linderman VF. Effect of DDT on testes and secondary sex characteristics of white leghorn cockerels. Proc Soc Exp Biol Med. 1950; 74: 48–51.
8. Bitman J, Cecil HC, Harris SJ, Fries GF. Estrogenic activity of o,pʹ-DDT in the mammalian uterus and avian oviduct. Science. 1968; 162: 371–372.
9. Welch RM, Levin W, Conney AH. Estrogenic action of DDT and its analogs. Toxicol Appl Pharmacol. 1969: 4; 358–367.
10. Carson R. Silent Spring. USA: Houghton Mifflin, 1962.
11. Colborn T, Dumanoski D, Myers JP. Our Stolen Future. Dutton, USA.1996.
12. Horiguchi T. Masculinization of female gastropod mollusks induced by organotin compounds, focusing on mechanism of actions of tributyltin and triphenyltin for development of imposex. Environ Sci. 2006; 13; 77–87.
13. Matthiessen P. Historical perspective on endocrine disruption in wildlife. Pure Appl Chem. 2003; 75: 2197–2206.
14. Guillette LJ, Gunderson MP. Alterations in development of reproductive and endocrine systems of wildlife populations exposed to endocrine-disrupting contaminants. Reproduction. 2001; 122; 857–864.
15. Jobling S, Nolan M, Tyler CR, Brighty G, Sumpter JP. Widespread sexual disruption in wild fish. Environ Sci Technol. 1998; 32: 2498–2506.
16. Harries JE, Janbakhsh A, Jobling S, Mattiessen P, Sumpter JP, Tyler CR. Estrogenic potency of effluent from two sewage treatment works in the United Kingdom. Environ Toxicol Chem. 1999; 18: 932–937.
17. Ratcliff DA. Decrease in eggshell weight in certain birds of prey. Nature. 1967; 215: 208–210.
18. Ratcliff DA. Changes attributable to pesticides in egg breakage frequency and eggshell thickness in some British birds. J Appl Ecol. 1970; 7: 67–115.
19. Lundholm CE. DDE-induced eggshell thinning in birds: effects of p,pʹ-DDE on the calcium and prostaglandin metabolism of the eggshell gland. Comp Biochem Physiol Part C Pharmacol Toxicol Endocrinol. 1997; 118: 113–128.
20. Bergman A, Heindel JJ, Jobling S, Kidd KA, Zoeller RT (editors). The state of the science of endocrine disrupting chemicals—2012. United Nations Environment Programme (UNEP) and World Health Organisation (WHO), 2013.
21. Dodds EC, Goldberg L, Lawson W, Robinson R. Estrogenic activity of certain synthetic compounds. Nature. 1938; 141: 247-248.
22. Stanczyk FZ, Archer DF, Bhavnani BR. Ethinyl estradiol and 17-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception. 2013; 87: 706-727.
23. Mattox JH, Shulkman LP. Combined oral hormone replacement therapy formulations. Am J Obstet Gynecol. 2001; 185: S38-S46.
24. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids - new mechanisms for old drugs. New Engl J Med. 2005; 353: 1711-1723.
25. The Recovery Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. New Eng J Med. 2021; 384: 693-704.
26. Lonning, P.E. (editor), Endocrinology and treatment of breast cancer. Clin Endocrinol Metab. 2004; 18: 1-130.
27. Smith OW. Diethylstilboestrol in the prevention and treatment of complications of pregnancy. Am J Obstet Gynecol. 1948; 56: 821-834.
28. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina: association of maternal stilboestrol therapy with tumor appearance in young women. New Engl J Med. 1971; 284: 878-881.
29. Harris RM, Waring RH. Diethylstilboestrol - a long-term legacy. Maturitas 2012; 72: 108-112.
30. Titus L, Hatch EE, Drake KM, et al, Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study. Reprod Toxicol. 2019; 84: 32-38.
31. Kalfa N, Paris F, Soyer-Gobillard MO, Daures JP, Sultan C. Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy: a multigenerational national cohort study. Fertility and Sterility. 2011; 95: 2574-2577.
32. Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol. 1902; 28: 325–353.
33. Moore DD. A conversation with Elwood Jensen. Ann Rev Physiol. 2012; 74: 1-11.
34. Jensen EV, Suzuki T, Kawashima T, Stumpf WE, Jungblut PW, DeSombre ER. A two-step mechanism for the interaction of estradiol with rat uterus. Proc Natl Acad Sci USA. 1968; 59: 632–638.
35. Toft D, Gorski J. A receptor molecule for estrogens: isolation from the rat uterus and preliminary characterization. Proc Natl Acad Sci USA. 1966; 55: 1574–1581.
36. Gorski J, Toft D, Shyamala G, Smith D, Notides A. Hormone receptors: studies on the interaction of estrogen with the uterus. Recent Prog Horm Res. 1968; 24: 45–80.
37. O’Malley BW, Means AR. Female steroid hormones and target cell nuclei. Science. 1974; 183: 610–620.
38. Greene GL, Closs LE, Fleming H, DeSombre ER, Jensen EV. Antibodies to estrogen receptor: immunochemical similarity of estrophilin from various mammalian species. Proc Natl Acad Sci USA. 1977; 74: 3681–3685.
39. Greene GL, Fitch FW, Jensen EV. Monoclonal antibodies to estrophilin: probes for the study of estrogen receptors. Proc Natl Acad Sci USA. 1980; 77: 157–161.
40. Green S, Walter P, Greene G, et al. Cloning of the human oestrogen receptor cDNA. J Steroid Biochem. 1986; 24: 77–83.
41. Parker, MG. (editor). Nuclear Hormone Receptors: Molecular Mechanisms, Cellular Functions, Clinical Abnormalities. Academic Press, 1991.
42. Nebert DW. Aryl hydrocarbon receptor (AHR): "pioneer member" of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of "sensors" of foreign and endogenous signals. Prog Lipid Res. 2017; 67: 38–57.
43. Acconcia F, Marino M. The effects of 17β-estradiol in cancer are mediated by estrogen receptor signaling at the plasma membrane. Front Physiol. 2011; 2: 1–8.
44. Soltysik K, Czekaj P, Membrane estrogen receptors—is it an alternative way of estrogen action?. J Physiol Pharmacol. 2013; 64: 129–142.
45. Alavian-Ghavanini A, Ruegg J. Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: From Mechanisms to Novel Test Methods. Basic Clin Pharmacol Toxicol. 2018; 122: 38-45.
46. Darbre PD. Overview of air pollution and endocrine disorders. Int J Gen Med. 2018; 11: 191-207.
47. Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL. The estrogen receptor binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci. 2000; 54: 138–153.
48. Rajapakse N, Silva E, Kortenkamp A. Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. Environ Health Perspect. 2002; 110: 917–921.
49. Silva E, Rajapakse N, Kortenkamp A. Something from “nothing”—eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol. 2002; 36: 1751–1756.
50. Kortenkamp A. Ten years of mixing cocktails: a review of combination effects of endocrine-disrupting chemicals. Environ Health Perspect. 2007; 115 (Suppl. 1): 98–105.
51. Charles AK, Darbre PD. Combinations of parabens at concentrations measured in human breast tissue can increase proliferation of MCF-7 human breast cancer cells. J Appl Toxicol. 2013; 33: 390–398.
52. Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP. Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999–2000. Environ Health Perspect. 2004; 112: 331–338.
53. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003–2004. Environ Health Perspect. 2008; 116: 39–44.
54. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Urinary concentrations of triclosan in the U.S. population: 2003–2004. Environ Health Perspect. 2008; 116: 303–307.
55. Calafat AM, Ye X, Wong LY, Bishop AM, Needham LL. Urinary concentrations of four parabens in the U.S. population: NHANES 2005–2006. Environ Health Perspect. 2010; 118: 679–685.
56. Calafat AM, Wong LY, Ye X, Reidy JA, Needham LL. Concentrations of the sunscreen agent benzophenone-3 in residents of the United States: National Health and Nutrition Examination Survey 2003–2004. Environ Health Perspect. 2008; 116: 893–897.
57. Tata JR. One hundred years of hormones. EMBO Reports. 2005; 6: 490-496.
58. Huhtaniemi I (editor). Encyclopaedia of Endocrine Diseases. 2nd edition. Elsevier, 2018. ISBN: 9780128121993
59. Jensen TK, Vierula M, Hjollund NH, et al. Semen quality among Danish and Finnish men attempting to conceive. The Danish first pregnancy planner study team. Eur J Endocrinol. 2000; 142: 47–52.
60. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001; 16: 972–978.
61. Barker DJP. Fetal origins of coronary heart disease. Brit Med J. 1995; 311: 171-174.
62. Schug TT, Janesick A, Blumberg B, Heindl JJ. Endocrine disrupting chemicals and disease susceptibility. J Steroid Biochem Mole Biol. 2011; 127: 204-215.
63. Nesan D, Kurrasch DM. Gestational exposure to common endocrine disrupting chemicals and their impact on neurodevelopment and behavior. Ann Rev Physiol. 2020; 82: 177-202.
64. Iguchi T, Sato T, Nakajima T, Miyagawa S, Takasugi N. New frontiers of developmental endocrinology opened by researchers connecting irreversible effects of sex hormones on developing organs. Differentiation (2020) (EPubaheadofprint).
65. Darbre PD. Endocrine disruptors and obesity. Curr Obes Rep. 2017; 6: 18-27.
66. Darbre P. EDCs and breast cancer cells. Adv Pharmacol. 2021; 92 (in press)
67. Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR, Lee DH. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev. 2012; 33: 378–455.
68. Burks H, Pashos N, Martin E, McLachlan J, Bunnell B, Burow M. Endocrine disruptors and the tumor microenvironment: a new paradigm in breast cancer biology. Mol Cell Endocrinol. 2017; 457: 13-19.
69. Colborn T, Clement C. Chemically-induced alterations in sexual and functional development: the wildlife/human connection. Princeton, NJ: Princeton Scientific Publishing Co Inc; 1992.
70. Report of the Proceedings of the European workshop on the impact of endocrine disrupters on human health and wildlife. Weybridge, UK. Report EUR17549 of the Environment and Climate Change Research Programme of DGXII of the European Commission. 1996.
71. European Environment Agency (EEA). The impacts of endocrine disrupters on wildlife, people and their environments. The Weybridge+15 (1996-2011) report. Publications Office of the European Union, Luxemburg, 2012. ISBN 978-92-9213-307-B.
72. Slama R, Bourguignon JP, Demeneix B, et al. Scientific issues relevant to setting regulatory criteria to identify endocrine-disrupting substances in the European Union. Environ Health Perspect. 2016; 124: 1497-1503.
73. Edidin DV, Levitsky LL. Prepubertal gynecomastia associated with estrogen-containing hair cream. Am J Dis Child. 1982; 136: 587–588.
74. Finkelstein JS, McCully WF, MacLaughlin DT, Godine JE, Crowley WF. The Mortician’s Mystery. New Engl J Med. 1988; 318: 961–965.
75. Bhat N, Rosato EF, Gupta PK. Gynecomastia in a mortician. A case report. Acta Cytol. 1990; 34: 31–34.
76. Felner EI, White PC. Prepubertal gynecomastia: indirect exposure to estrogen cream. Pediatrics. 2000; 105 (e55): 1–3.
77. Henley DV, Lipson N, Korach KS, Bloch CA. Prepubertal gynecomastia linked to lavender and tea tree oils. New Engl J Med. 2007; 356: 479–485.
78. Thom R. Structural Stability and Morphogenesis: An Outline of a General Theory of Models. CRC Press (2018) (available online through search of the title) – originally published in French in 1972 by WA. Benjamin, Inc.
2. Darbre PDD (editor). Endocrine Disruption and Human Health, Elsevier, 2015 (second edition pending autumn 2021).
3. McNutt SH, Purwin P, Murray C. Vulvo-vaginitis in swine: preliminary report. J Am Vet Med Assoc. 1928; 73: 484.
4. Bennets H, Underwood EJ, Shier FL. A specific breeding problem of sheep on subterranean clover pasture in Western Australia. Aust Vet J. 1946; 22: 2-12.
5. Bennett JW, Klich M. Mycotoxins. Clin Microbiol Rev. 2003; 16: 497-516.
6. Woods, H.F. (chairman), Phytoestrogens and health. Crown copyright UK, 2003.
7. Burlington H, Linderman VF. Effect of DDT on testes and secondary sex characteristics of white leghorn cockerels. Proc Soc Exp Biol Med. 1950; 74: 48–51.
8. Bitman J, Cecil HC, Harris SJ, Fries GF. Estrogenic activity of o,pʹ-DDT in the mammalian uterus and avian oviduct. Science. 1968; 162: 371–372.
9. Welch RM, Levin W, Conney AH. Estrogenic action of DDT and its analogs. Toxicol Appl Pharmacol. 1969: 4; 358–367.
10. Carson R. Silent Spring. USA: Houghton Mifflin, 1962.
11. Colborn T, Dumanoski D, Myers JP. Our Stolen Future. Dutton, USA.1996.
12. Horiguchi T. Masculinization of female gastropod mollusks induced by organotin compounds, focusing on mechanism of actions of tributyltin and triphenyltin for development of imposex. Environ Sci. 2006; 13; 77–87.
13. Matthiessen P. Historical perspective on endocrine disruption in wildlife. Pure Appl Chem. 2003; 75: 2197–2206.
14. Guillette LJ, Gunderson MP. Alterations in development of reproductive and endocrine systems of wildlife populations exposed to endocrine-disrupting contaminants. Reproduction. 2001; 122; 857–864.
15. Jobling S, Nolan M, Tyler CR, Brighty G, Sumpter JP. Widespread sexual disruption in wild fish. Environ Sci Technol. 1998; 32: 2498–2506.
16. Harries JE, Janbakhsh A, Jobling S, Mattiessen P, Sumpter JP, Tyler CR. Estrogenic potency of effluent from two sewage treatment works in the United Kingdom. Environ Toxicol Chem. 1999; 18: 932–937.
17. Ratcliff DA. Decrease in eggshell weight in certain birds of prey. Nature. 1967; 215: 208–210.
18. Ratcliff DA. Changes attributable to pesticides in egg breakage frequency and eggshell thickness in some British birds. J Appl Ecol. 1970; 7: 67–115.
19. Lundholm CE. DDE-induced eggshell thinning in birds: effects of p,pʹ-DDE on the calcium and prostaglandin metabolism of the eggshell gland. Comp Biochem Physiol Part C Pharmacol Toxicol Endocrinol. 1997; 118: 113–128.
20. Bergman A, Heindel JJ, Jobling S, Kidd KA, Zoeller RT (editors). The state of the science of endocrine disrupting chemicals—2012. United Nations Environment Programme (UNEP) and World Health Organisation (WHO), 2013.
21. Dodds EC, Goldberg L, Lawson W, Robinson R. Estrogenic activity of certain synthetic compounds. Nature. 1938; 141: 247-248.
22. Stanczyk FZ, Archer DF, Bhavnani BR. Ethinyl estradiol and 17-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception. 2013; 87: 706-727.
23. Mattox JH, Shulkman LP. Combined oral hormone replacement therapy formulations. Am J Obstet Gynecol. 2001; 185: S38-S46.
24. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids - new mechanisms for old drugs. New Engl J Med. 2005; 353: 1711-1723.
25. The Recovery Collaborative Group. Dexamethasone in hospitalized patients with Covid-19. New Eng J Med. 2021; 384: 693-704.
26. Lonning, P.E. (editor), Endocrinology and treatment of breast cancer. Clin Endocrinol Metab. 2004; 18: 1-130.
27. Smith OW. Diethylstilboestrol in the prevention and treatment of complications of pregnancy. Am J Obstet Gynecol. 1948; 56: 821-834.
28. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina: association of maternal stilboestrol therapy with tumor appearance in young women. New Engl J Med. 1971; 284: 878-881.
29. Harris RM, Waring RH. Diethylstilboestrol - a long-term legacy. Maturitas 2012; 72: 108-112.
30. Titus L, Hatch EE, Drake KM, et al, Reproductive and hormone-related outcomes in women whose mothers were exposed in utero to diethylstilbestrol (DES): A report from the US National Cancer Institute DES Third Generation Study. Reprod Toxicol. 2019; 84: 32-38.
31. Kalfa N, Paris F, Soyer-Gobillard MO, Daures JP, Sultan C. Prevalence of hypospadias in grandsons of women exposed to diethylstilbestrol during pregnancy: a multigenerational national cohort study. Fertility and Sterility. 2011; 95: 2574-2577.
32. Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol. 1902; 28: 325–353.
33. Moore DD. A conversation with Elwood Jensen. Ann Rev Physiol. 2012; 74: 1-11.
34. Jensen EV, Suzuki T, Kawashima T, Stumpf WE, Jungblut PW, DeSombre ER. A two-step mechanism for the interaction of estradiol with rat uterus. Proc Natl Acad Sci USA. 1968; 59: 632–638.
35. Toft D, Gorski J. A receptor molecule for estrogens: isolation from the rat uterus and preliminary characterization. Proc Natl Acad Sci USA. 1966; 55: 1574–1581.
36. Gorski J, Toft D, Shyamala G, Smith D, Notides A. Hormone receptors: studies on the interaction of estrogen with the uterus. Recent Prog Horm Res. 1968; 24: 45–80.
37. O’Malley BW, Means AR. Female steroid hormones and target cell nuclei. Science. 1974; 183: 610–620.
38. Greene GL, Closs LE, Fleming H, DeSombre ER, Jensen EV. Antibodies to estrogen receptor: immunochemical similarity of estrophilin from various mammalian species. Proc Natl Acad Sci USA. 1977; 74: 3681–3685.
39. Greene GL, Fitch FW, Jensen EV. Monoclonal antibodies to estrophilin: probes for the study of estrogen receptors. Proc Natl Acad Sci USA. 1980; 77: 157–161.
40. Green S, Walter P, Greene G, et al. Cloning of the human oestrogen receptor cDNA. J Steroid Biochem. 1986; 24: 77–83.
41. Parker, MG. (editor). Nuclear Hormone Receptors: Molecular Mechanisms, Cellular Functions, Clinical Abnormalities. Academic Press, 1991.
42. Nebert DW. Aryl hydrocarbon receptor (AHR): "pioneer member" of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of "sensors" of foreign and endogenous signals. Prog Lipid Res. 2017; 67: 38–57.
43. Acconcia F, Marino M. The effects of 17β-estradiol in cancer are mediated by estrogen receptor signaling at the plasma membrane. Front Physiol. 2011; 2: 1–8.
44. Soltysik K, Czekaj P, Membrane estrogen receptors—is it an alternative way of estrogen action?. J Physiol Pharmacol. 2013; 64: 129–142.
45. Alavian-Ghavanini A, Ruegg J. Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: From Mechanisms to Novel Test Methods. Basic Clin Pharmacol Toxicol. 2018; 122: 38-45.
46. Darbre PD. Overview of air pollution and endocrine disorders. Int J Gen Med. 2018; 11: 191-207.
47. Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL. The estrogen receptor binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci. 2000; 54: 138–153.
48. Rajapakse N, Silva E, Kortenkamp A. Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. Environ Health Perspect. 2002; 110: 917–921.
49. Silva E, Rajapakse N, Kortenkamp A. Something from “nothing”—eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol. 2002; 36: 1751–1756.
50. Kortenkamp A. Ten years of mixing cocktails: a review of combination effects of endocrine-disrupting chemicals. Environ Health Perspect. 2007; 115 (Suppl. 1): 98–105.
51. Charles AK, Darbre PD. Combinations of parabens at concentrations measured in human breast tissue can increase proliferation of MCF-7 human breast cancer cells. J Appl Toxicol. 2013; 33: 390–398.
52. Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP. Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999–2000. Environ Health Perspect. 2004; 112: 331–338.
53. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003–2004. Environ Health Perspect. 2008; 116: 39–44.
54. Calafat AM, Ye X, Wong LY, Reidy JA, Needham LL. Urinary concentrations of triclosan in the U.S. population: 2003–2004. Environ Health Perspect. 2008; 116: 303–307.
55. Calafat AM, Ye X, Wong LY, Bishop AM, Needham LL. Urinary concentrations of four parabens in the U.S. population: NHANES 2005–2006. Environ Health Perspect. 2010; 118: 679–685.
56. Calafat AM, Wong LY, Ye X, Reidy JA, Needham LL. Concentrations of the sunscreen agent benzophenone-3 in residents of the United States: National Health and Nutrition Examination Survey 2003–2004. Environ Health Perspect. 2008; 116: 893–897.
57. Tata JR. One hundred years of hormones. EMBO Reports. 2005; 6: 490-496.
58. Huhtaniemi I (editor). Encyclopaedia of Endocrine Diseases. 2nd edition. Elsevier, 2018. ISBN: 9780128121993
59. Jensen TK, Vierula M, Hjollund NH, et al. Semen quality among Danish and Finnish men attempting to conceive. The Danish first pregnancy planner study team. Eur J Endocrinol. 2000; 142: 47–52.
60. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod. 2001; 16: 972–978.
61. Barker DJP. Fetal origins of coronary heart disease. Brit Med J. 1995; 311: 171-174.
62. Schug TT, Janesick A, Blumberg B, Heindl JJ. Endocrine disrupting chemicals and disease susceptibility. J Steroid Biochem Mole Biol. 2011; 127: 204-215.
63. Nesan D, Kurrasch DM. Gestational exposure to common endocrine disrupting chemicals and their impact on neurodevelopment and behavior. Ann Rev Physiol. 2020; 82: 177-202.
64. Iguchi T, Sato T, Nakajima T, Miyagawa S, Takasugi N. New frontiers of developmental endocrinology opened by researchers connecting irreversible effects of sex hormones on developing organs. Differentiation (2020) (EPubaheadofprint).
65. Darbre PD. Endocrine disruptors and obesity. Curr Obes Rep. 2017; 6: 18-27.
66. Darbre P. EDCs and breast cancer cells. Adv Pharmacol. 2021; 92 (in press)
67. Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR, Lee DH. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev. 2012; 33: 378–455.
68. Burks H, Pashos N, Martin E, McLachlan J, Bunnell B, Burow M. Endocrine disruptors and the tumor microenvironment: a new paradigm in breast cancer biology. Mol Cell Endocrinol. 2017; 457: 13-19.
69. Colborn T, Clement C. Chemically-induced alterations in sexual and functional development: the wildlife/human connection. Princeton, NJ: Princeton Scientific Publishing Co Inc; 1992.
70. Report of the Proceedings of the European workshop on the impact of endocrine disrupters on human health and wildlife. Weybridge, UK. Report EUR17549 of the Environment and Climate Change Research Programme of DGXII of the European Commission. 1996.
71. European Environment Agency (EEA). The impacts of endocrine disrupters on wildlife, people and their environments. The Weybridge+15 (1996-2011) report. Publications Office of the European Union, Luxemburg, 2012. ISBN 978-92-9213-307-B.
72. Slama R, Bourguignon JP, Demeneix B, et al. Scientific issues relevant to setting regulatory criteria to identify endocrine-disrupting substances in the European Union. Environ Health Perspect. 2016; 124: 1497-1503.
73. Edidin DV, Levitsky LL. Prepubertal gynecomastia associated with estrogen-containing hair cream. Am J Dis Child. 1982; 136: 587–588.
74. Finkelstein JS, McCully WF, MacLaughlin DT, Godine JE, Crowley WF. The Mortician’s Mystery. New Engl J Med. 1988; 318: 961–965.
75. Bhat N, Rosato EF, Gupta PK. Gynecomastia in a mortician. A case report. Acta Cytol. 1990; 34: 31–34.
76. Felner EI, White PC. Prepubertal gynecomastia: indirect exposure to estrogen cream. Pediatrics. 2000; 105 (e55): 1–3.
77. Henley DV, Lipson N, Korach KS, Bloch CA. Prepubertal gynecomastia linked to lavender and tea tree oils. New Engl J Med. 2007; 356: 479–485.
78. Thom R. Structural Stability and Morphogenesis: An Outline of a General Theory of Models. CRC Press (2018) (available online through search of the title) – originally published in French in 1972 by WA. Benjamin, Inc.