Endocrinol Metab.  2018 Mar;33(1):44-52. 10.3803/EnM.2018.33.1.44.

Evidence of the Possible Harm of Endocrine-Disrupting Chemicals in Humans: Ongoing Debates and Key Issues

• Lee DH

• KMID: 2407119
• DOI: http://doi.org/10.3803/EnM.2018.33.1.44

Abstract

Evidence has emerged that endocrine-disrupting chemicals (EDCs) can produce adverse effects, even at low doses that are assumed safe. However, systemic reviews and meta-analyses focusing on human studies, especially of EDCs with short half-lives, have demonstrated inconsistent results. Epidemiological studies have insuperable methodological limitations, including the unpredictable net effects of mixtures, non-monotonic dose-response relationships, the non-existence of unexposed groups, and the low reliability of exposure assessment. Thus, despite increases in EDC-linked diseases, traditional epidemiological studies based on individual measurements of EDCs in bio-specimens may fail to provide consistent results. The exposome has been suggested as a promising approach to address the uncertainties surrounding human studies, but it is never free from these methodological issues. Although exposure to EDCs during critical developmental periods is a major concern, continuous exposure to EDCs during non-critical periods is also harmful. Indeed, the evolutionary aspects of epigenetic programming triggered by EDCs during development should be considered because it is a key mechanism for developmental plasticity. Presently, living without EDCs is impossible due to their omnipresence. Importantly, there are lifestyles which can increase the excretion of EDCs or mitigate their harmful effects through the activation of mitohormesis or xenohormesis. Effectiveness of lifestyle interventions should be evaluated as practical ways against EDCs in the real world.

Keyword

Chemical mixtures; Endocrine-disrupting chemicals; Exposure assessment; Epidemiology; Evolution; Metabolism-disrupting chemicals; Non-monotonic dose response relationship; Predictive adaptive response hypothesis; Persistent organic pollutants; Reliability

MeSH Terms

Epidemiologic Studies
Epidemiology
Epigenomics
Humans*
Life Style
Plastics
Plastics

Figure

• 

  Fig. 1 Issues in human studies of endocrine-disrupting chemicals (EDCs) and practical recommendations for clinicians and the public. Despite the increasing trend of EDC-linked diseases, it is difficult to find consistent human evidence on the harms of EDCs, especially the short-lived EDCs currently in wide use, due to critical methodological issues. In the case of human studies, possible research areas are limited. Both early-life exposure during critical periods and continuous exposure during non-critical periods can be harmful to humans. However, epigenetic programming induced during critical periods is a key to developmental plasticity and evolutionary aspects should be considered. Harms due to continuous exposure during the non-critical period may be mitigated by adopting lifestyle measures that counteract the harmful effects of EDCs. Effectiveness of lifestyle interventions should be evaluated as practical ways against EDCs in the real world.

Reference

1. Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM, et al. Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. 2009; 30:293–342.

2. Gore AC, Chappell VA, Fenton SE, Flaws JA, Nadal A, Prins GS, et al. EDC-2: the Endocrine Society's second scientific statement on endocrine-disrupting chemicals. Endocr Rev. 2015; 36:E1–E150.

3. The Endocrine Disruption Exchange. TEDX list of potential endocrine disruptors [Internet]. Eckert: TEDX;2017. cited 2018 Feb 21. Available from: https://endocrinedisruption.org/.

4. Iavicoli I, Fontana L, Leso V, Bergamaschi A. The effects of nanomaterials as endocrine disruptors. Int J Mol Sci. 2013; 14:16732–16801.

5. World Health Organization. The state-of-the-science of endocrine disrupting chemicals 2012 [Internet]. Geneva: WHO;c2018. cited 2018 Feb 21. Available from: http://www.who.int/ceh/publications/endocrine/en/index.html.

6. Colborn T, vom Saal FS, Soto AM. Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect. 1993; 101:378–384.

7. Fry DM. Reproductive effects in birds exposed to pesticides and industrial chemicals. Environ Health Perspect. 1995; 103:Suppl 7. 165–171.

8. Zoeller TR. Environmental chemicals targeting thyroid. Hormones (Athens). 2010; 9:28–40.

9. Scsukova S, Rollerova E, Bujnakova Mlynarcikova A. Impact of endocrine disrupting chemicals on onset and development of female reproductive disorders and hormone-related cancer. Reprod Biol. 2016; 16:243–254.

10. Parent AS, Naveau E, Gerard A, Bourguignon JP, Westbrook GL. Early developmental actions of endocrine disruptors on the hypothalamus, hippocampus, and cerebral cortex. J Toxicol Environ Health B Crit Rev. 2011; 14:328–345.

11. Heindel JJ, Blumberg B, Cave M, Machtinger R, Mantovani A, Mendez MA, et al. Metabolism disrupting chemicals and metabolic disorders. Reprod Toxicol. 2017; 68:3–33.

12. Kretschmer XC, Baldwin WS. CAR and PXR: xenosensors of endocrine disrupters? Chem Biol Interact. 2005; 155:111–128.

13. Kortenkamp A, Martin O, Evans R, Orton F, McKinlay R, Rosivatz E, et al. Response to a critique of the European Commission Document, “State of the Art Assessment of Endocrine Disrupters” by Rhomberg and colleagues: letter to the editor. Crit Rev Toxicol. 2012; 42:787–789.

14. Gore AC, Balthazart J, Bikle D, Carpenter DO, Crews D, Czernichow P, et al. Policy decisions on endocrine disruptors should be based on science across disciplines: a response to Dietrich et al. Eur J Endocrinol. 2013; 169:E1–E4.

15. Bergman A, Andersson AM, Becher G, van den Berg M, Blumberg B, Bjerregaard P, et al. Science and policy on endocrine disrupters must not be mixed: a reply to a “common sense” intervention by toxicology journal editors. Environ Health. 2013; 12:69.

16. Zoeller RT, Bergman A, Becher G, Bjerregaard P, Bornman R, Brandt I, et al. A path forward in the debate over health impacts of endocrine disrupting chemicals. Environ Health. 2014; 13:118.

17. Bergman A, Becher G, Blumberg B, Bjerregaard P, Bornman R, Brandt I, et al. Manufacturing doubt about endocrine disrupter science: a rebuttal of industry-sponsored critical comments on the UNEP/WHO report “State of the Science of Endocrine Disrupting Chemicals 2012”. Regul Toxicol Pharmacol. 2015; 73:1007–1017.

18. Dietrich DR, von Aulock S, Marquardt H, Blaauboer B, Dekant W, Kehrer J, et al. Scientifically unfounded precaution drives European Commission's recommendations on EDC regulation, while defying common sense, well-established science and risk assessment principles. Toxicol In Vitro. 2013; 27:2110–2114.

19. Rhomberg LR, Goodman JE, Foster WG, Borgert CJ, Van Der Kraak G. A critique of the European Commission document, “State of the Art Assessment of Endocrine Disrupters”. Crit Rev Toxicol. 2012; 42:465–473.

20. Lamb JC 4th, Boffetta P, Foster WG, Goodman JE, Hentz KL, Rhomberg LR, et al. Comments on the opinions published by Bergman et al. (2015) on Critical Comments on the WHO-UNEP State of the Science of Endocrine Disrupting Chemicals (Lamb et al., 2014). Regul Toxicol Pharmacol. 2015; 73:754–757.

21. Lamb JC 4th, Boffetta P, Foster WG, Goodman JE, Hentz KL, Rhomberg LR, et al. Critical comments on the WHOUNEP State of the Science of Endocrine Disrupting Chemicals: 2012. Regul Toxicol Pharmacol. 2014; 69:22–40.

22. Leonardi A, Cofini M, Rigante D, Lucchetti L, Cipolla C, Penta L, et al. The effect of bisphenol a on puberty: a critical review of the medical literature. Int J Environ Res Public Health. 2017; 14:E1044.

23. Lakind JS, Goodman M, Mattison DR. Bisphenol A and indicators of obesity, glucose metabolism/type 2 diabetes and cardiovascular disease: a systematic review of epidemiologic research. Crit Rev Toxicol. 2014; 44:121–150.

24. Goodman M, Lakind JS, Mattison DR. Do phthalates act as obesogens in humans? A systematic review of the epidemiological literature. Crit Rev Toxicol. 2014; 44:151–175.

25. Goodman M, Naiman DQ, LaKind JS. Systematic review of the literature on triclosan and health outcomes in humans. Crit Rev Toxicol. 2018; 48:1–51.

26. Bonde JP, Flachs EM, Rimborg S, Glazer CH, Giwercman A, Ramlau-Hansen CH, et al. The epidemiologic evidence linking prenatal and postnatal exposure to endocrine disrupting chemicals with male reproductive disorders: a systematic review and meta-analysis. Hum Reprod Update. 2016; 23:104–125.

27. Trasande L, Zoeller RT, Hass U, Kortenkamp A, Grandjean P, Myers JP, et al. Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis. Andrology. 2016; 4:565–572.

28. Attina TM, Hauser R, Sathyanarayana S, Hunt PA, Bourguignon JP, Myers JP, et al. Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis. Lancet Diabetes Endocrinol. 2016; 4:996–1003.

29. Dietrich DR. EU safety regulations: don’t mar legislation with pseudoscience. Nature. 2016; 535:355.

30. Bond GG, Dietrich DR. Human cost burden of exposure to endocrine disrupting chemicals. A critical review. Arch Toxicol. 2017; 91:2745–2762.

31. Lee DH, Jacobs DR Jr. Methodological issues in human studies of endocrine disrupting chemicals. Rev Endocr Metab Disord. 2015; 16:289–297.

32. 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.

33. Carnevali O, Notarstefano V, Olivotto I, Graziano M, Gallo P, Di Marco Pisciottano I, et al. Dietary administration of EDC mixtures: a focus on fish lipid metabolism. Aquat Toxicol. 2017; 185:95–104.

34. Sarria MP, Santos MM, Reis-Henriques MA, Vieira NM, Monteiro NM. The unpredictable effects of mixtures of androgenic and estrogenic chemicals on fish early life. Environ Int. 2011; 37:418–424.

35. Ribeiro E, Ladeira C, Viegas S. EDCs mixtures: a stealthy hazard for human health? Toxics. 2017; 5:E5.

36. Hu Y, Wang R, Xiang Z, Qian W, Han X, Li D. Antagonistic effects of a mixture of low-dose nonylphenol and di-n-butyl phthalate (monobutyl phthalate) on the Sertoli cells and serum reproductive hormones in prepubertal male rats in vitro and in vivo. PLoS One. 2014; 9:e93425.

37. Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR Jr, Lee DH, et al. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev. 2012; 33:378–455.

38. Lagarde F, Beausoleil C, Belcher SM, Belzunces LP, Emond C, Guerbet M, et al. Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment. Environ Health. 2015; 14:13.

39. Calabrese EJ, Mattson MP. How does hormesis impact biology, toxicology, and medicine? NPJ Aging Mech Dis. 2017; 3:13.

40. Pastor-Barriuso R, Fernandez MF, Castano-Vinyals G, Whelan D, Perez-Gomez B, Llorca J, et al. Total effective xenoestrogen burden in serum samples and risk for breast cancer in a population-based multicase-control study in Spain. Environ Health Perspect. 2016; 124:1575–1582.

41. Lee DH, Steffes MW, Sjodin A, Jones RS, Needham LL, Jacobs DR Jr. Low dose of some persistent organic pollutants predicts type 2 diabetes: a nested case-control study. Environ Health Perspect. 2010; 118:1235–1242.

42. Lee DH, Steffes MW, Sjodin A, Jones RS, Needham LL, Jacobs DR Jr. Low dose organochlorine pesticides and polychlorinated biphenyls predict obesity, dyslipidemia, and insulin resistance among people free of diabetes. PLoS One. 2011; 6:e15977.

43. Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, et al. Low-level environmental lead exposure and children’s intellectual function: an international pooled analysis. Environ Health Perspect. 2005; 113:894–899.

44. Vlaanderen J, Portengen L, Rothman N, Lan Q, Kromhout H, Vermeulen R. Flexible meta-regression to assess the shape of the benzene-leukemia exposure-response curve. Environ Health Perspect. 2010; 118:526–532.

45. Pinault L, Tjepkema M, Crouse DL, Weichenthal S, van Donkelaar A, Martin RV, et al. Risk estimates of mortality attributed to low concentrations of ambient fine particulate matter in the Canadian community health survey cohort. Environ Health. 2016; 15:18.

46. LaKind JS, Sobus JR, Goodman M, Barr DB, Furst P, Albertini RJ, et al. A proposal for assessing study quality: Biomonitoring, Environmental Epidemiology, and Short-lived Chemicals (BEES-C) instrument. Environ Int. 2014; 73:195–207.

47. Li Z, Romanoff LC, Lewin MD, Porter EN, Trinidad DA, Needham LL, et al. Variability of urinary concentrations of polycyclic aromatic hydrocarbon metabolite in general population and comparison of spot, first-morning, and 24-h void sampling. J Expo Sci Environ Epidemiol. 2010; 20:526–535.

48. Preau JL Jr, Wong LY, Silva MJ, Needham LL, Calafat AM. Variability over 1 week in the urinary concentrations of metabolites of diethyl phthalate and di(2-ethylhexyl) phthalate among eight adults: an observational study. Environ Health Perspect. 2010; 118:1748–1754.

49. Ye X, Wong LY, Bishop AM, Calafat AM. Variability of urinary concentrations of bisphenol A in spot samples, first morning voids, and 24-hour collections. Environ Health Perspect. 2011; 119:983–988.

50. Perrier F, Giorgis-Allemand L, Slama R, Philippat C. Within-subject pooling of biological samples to reduce exposure misclassification in biomarker-based studies. Epidemiology. 2016; 27:378–388.

51. Messerlian C, Martinez RM, Hauser R, Baccarelli AA. ‘Omics’ and endocrine-disrupting chemicals: new paths forward. Nat Rev Endocrinol. 2017; 13:740–748.

52. Vrijheid M, Slama R, Robinson O, Chatzi L, Coen M, van den, et al. The human early-life exposome (HELIX): project rationale and design. Environ Health Perspect. 2014; 122:535–544.

53. Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. 2012; 13:97–109.

54. Taylor KW, Joubert BR, Braun JM, Dilworth C, Gennings C, Hauser R, et al. Statistical approaches for assessing health effects of environmental chemical mixtures in epidemiology: lessons from an innovative workshop. Environ Health Perspect. 2016; 124:A227–A229.

55. Agier L, Portengen L, Chadeau-Hyam M, Basagana X, Giorgis-Allemand L, Siroux V, et al. A systematic comparison of linear regression-based statistical methods to assess exposome-health associations. Environ Health Perspect. 2016; 124:1848–1856.

56. Lee DH, Porta M, Jacobs DR Jr, Vandenberg LN. Chlorinated persistent organic pollutants, obesity, and type 2 diabetes. Endocr Rev. 2014; 35:557–601.

57. Taylor KW, Novak RF, Anderson HA, Birnbaum LS, Blystone C, Devito M, et al. Evaluation of the association between persistent organic pollutants (POPs) and diabetes in epidemiological studies: a national toxicology program workshop review. Environ Health Perspect. 2013; 121:774–783.

58. Lim S, Cho YM, Park KS, Lee HK. Persistent organic pollutants, mitochondrial dysfunction, and metabolic syndrome. Ann N Y Acad Sci. 2010; 1201:166–176.

59. Kortenkamp A. Endocrine disruptors: the burden of endocrine-disrupting chemicals in the USA. Nat Rev Endocrinol. 2016; 13:6–7.

60. Hanson MA, Gluckman PD. Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev. 2014; 94:1027–1076.

61. Ravelli AC, van der, Michels RP, Osmond C, Barker DJ, Hales CN, et al. Glucose tolerance in adults after prenatal exposure to famine. Lancet. 1998; 351:173–177.

62. Stanner SA, Yudkin JS. Fetal programming and the Leningrad Siege study. Twin Res. 2001; 4:287–292.

63. Bateson P, Gluckman P, Hanson M. The biology of developmental plasticity and the predictive adaptive response hypothesis. J Physiol. 2014; 592:2357–2368.

64. Kusminski CM, Holland WL, Sun K, Park J, Spurgin SB, Lin Y, et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med. 2012; 18:1539–1549.

65. Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, et al. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009; 29:4467–4483.

66. Lee YM, Kim KS, Jacobs DR Jr, Lee DH. Persistent organic pollutants in adipose tissue should be considered in obesity research. Obes Rev. 2017; 18:129–139.

67. Frye CA, Bo E, Calamandrei G, Calza L, Dessi-Fulgheri F, Fernandez M, et al. Endocrine disrupters: a review of some sources, effects, and mechanisms of actions on behaviour and neuroendocrine systems. J Neuroendocrinol. 2012; 24:144–159.

68. Kim SA, Lee YM, Choi JY, Jacobs DR Jr, Lee DH. Evolutionarily adapted hormesis-inducing stressors can be a practical solution to mitigate harmful effects of chronic exposure to low dose chemical mixtures. Environ Pollut. 2018; 233:725–734.

69. Hutter HP, Kundi M, Hohenblum P, Scharf S, Shelton JF, Piegler K, et al. Life without plastic: a family experiment and biomonitoring study. Environ Res. 2016; 150:639–644.