Best Practice & Research Clinical Endocrinology & Metabolism
Volume 20, Issue 1 , Pages 145-165 , March 2006

Regulation of endocrine-disrupting chemicals: Critical overview and deficiencies in toxicology and risk assessment for human health

  • Philip W. Harvey, BSc (Hons), PhD, CBiol, MIBiol (Registered Toxicologist)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +44 1423 848421; Fax: +44 1423 569595.
    • ,
  • David J. Everett, BSc (Hons), CBiol, FIBiol (Registered Toxicologist)

References 

  1. Harvey PW, Rush KC, Cockburn A. Endocrine and Hormonal Toxicology. Chichester: Wiley; 1999;
  2. Rastogi SC, Schouten A, de Kruijf N, Weijland JW. Contents of methyl-, ethyl-, propyl-, butyl- and benzylparaben in cosmetic products. Contact Dermatitis. 1995;32:28–30
  3. Rastogi SC. Analytical control of preservative labelling on skin creams. Contact Dermatitis. 2000;43:339–343
  4. Gruvberger B, Bruze M, Tammela M. Preservatives in moisturisers on the Swedish market. Acta Dermato-Venereologica. 1998;78:52–56
  5. Dodge JA. Natural and anthropogenic environmental oestrogens: the scientific basis for risk assessment. Structure/ activity relationships. Pure and Applied Chemistry. 1998;70:1725–1733
  6. Hong H, Tong W, Fang H, et al. Prediction of estrogen receptor binding for 58,000 chemicals using an integrated system of a tree based model with structural alerts. Environmental Health Perspectives. 2002;110:29–36
  7. Gad SC. Regulatory Toxicology. 2nd edn. London: Taylor and Francis; 2001;
  8. Cockburn A, Leist K-H. Current and regulatory trends in endocrine and hormonal toxicology. In:  Harvey PW,  Rush KC,  Cockburn A editor. Endocrine and Hormonal Toxicology. Chichester: Wiley; 1999;p. 507–534
  9. EDSTAC. Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) Final Report, August 1998. United States Environmental Protection Agency. http://www.epa.gov/scipoly/oscpendo/history/finalrpt.htm; 1998.
  10. Ashby J, Lefevre PA. The peripubertal male rat assay as an alternative to the Hershberger castrated male rat assay for the detection of anti-androgens, oestrogens and metabolic modulators. Journal of Applied Toxicology. 2000;20:35–47
  11. Ashby J. Testing for endocrine disruption post-EDSTAC: extrapolation of low dose rodent effects to humans. Toxicology Letters. 2001;120:233–242
  12. Harrison PTC. Endocrine disrupters and human health. Current research will establish baseline indices. British Medical Journal. 2001;323:1317–1318
  13. Harvey PW. Parabens, oestrogenicity, underarm cosmetics and breast cancer: a perspective on a hypothesis. Journal of Applied Toxicology. 2003;23:285–288
  14. Harvey PW, Darbre P. Endocrine disrupters and human health: could oestrogenic chemicals in body care cosmetics affect breast cancer incidence in women? A review of evidence and call for further research. Journal of Applied Toxicology. 2004;24:167–176
  15. Sharpe M, Irvine DS. How strong is the evidence of a link between environmental chemicals and adverse effects on human reproductive health?. British Medical Journal. 2004;328:447–451
  16. USEPA. United States Environmental Protection Agency. Endocrine disruptor screening program: early priority setting activities. http://www.epa.gov/scipoly/oscpendo/prioritysetting/activities.htm..
  17. European Commission. Environment Directorate General. Endocrine Disrupters Website. http://europa.eu.int/comm/environment/endocrine/strategy/substances_en.htm.
  18. Wason S, Pohlmeyer-Esch G, Pallen C, et al. 17 alpha-methyltestosterone: 28 day oral toxicity study in the rat based on the ‘Enhanced OECD Test Guideline 407’ to detect endocrine effects. Toxicology. 2003;192:119–137
  19. Kunimatsu T, Yamada T, Miyata K, et al. Evaluation for reliability and feasibility of the draft protocol for the enhanced rat 28-day subacute study (OECD Guideline 407) using androgen antagonist flutamide. Toxicology. 2004;200:77–89
  20. Andrews P, Freyberger A, Hartmann E, et al. Sensitive detection of the endocrine effects of the estrogen analogue ethinylestradiol using a modified enhanced subacute rat study protocol (OECD Test Guideline no. 407). Archives of Toxicology. 2002;76:194–202
  21. Kennel P, Pallen C, Barale-Thomas E, et al. Tamoxifen: 28-day oral toxicity study in the rat based on the Enhanced OECD Test Guideline 407 to detect endocrine effects. Archives of Toxicology. 2003;77:487–499
  22. Yamasaki K, Tago Y, Nagai K, et al. Comparison of toxicity studies based on the draft protocol for the ‘Enhanced OECD test guideline no. 407’ and the reasearch protocol ‘Pubertal development and thyroid function in immature male rats’ with 6-n-propyl-2-thiouracil. Archives of Toxicology. 2002;76:495–501
  23. Mellert W, Deckardt K, Walter J, et al. Detection of endocrine-modulating effects of the antithyroid acting drug 6-propyl-2-thoiuracil in rats, based on the ‘Enhanced OECD test guideline 407’. Regulatory Toxicology and Pharmacology. 2003;38:368–377
  24. Gelbke HP, Kayser M, Poole A. OECD test strategies and methods for endocrine disruptors. Toxicology. 2004;205:17–25
  25. Worth A, Balls M. Alternative (non-animal) methods for chemical testing: current status and future prospects. A report prepared by ECVAM and the ECVAM working group on chemicals. Endocrine disruption in humans. Alternatives to Laboratory Animals. 2002;30(supplement 1):103–113[chapter 11]
  26. Dandrea J, Combes RD. A survey of stakeholder organisations on the proposed new European chemical policy. Alternatives to Laboratory Animals. 2003;31:501–528
  27. Combes RD. Peer review of validation studies: an assessment of the role of the OECD by reference to the validation of the uterotrophic assay for endocrine disruptors. Alternatives to Laboratory Animals. 2004;32:111–117
  28. Harvey PW, Everett DJ. The adrenal cortex and steroidogenesis as cellular and molecular targets for toxicity: critical omissions from regulatory endocrine disrupter screening strategies for human health?. Journal of Applied Toxicology. 2003;23:81–87
  29. Combes RD. The case for taking account of metabolism when testing for potential endocrine disruptors in vitro. ALTA. 2004;32:121–135
  30. Harvey PW, Johnson I. Approaches to the assessment of toxicity data with endpoints related to endocrine disruption. Journal of Applied Toxicology. 2002;22:241–247
  31. Harvey PW, Rush KC, Cockburn A. Endocrine and hormonal toxicology: an integrated mechanistic and target system approach. In:  Harvey PW,  Rush KC,  Cockburn A editor. Endocrine and Hormonal Toxicology. Chichester: Wiley; 1999;p. 3–11
  32. Ribelin WE. The effects of drugs and chemicals upon the structure of the adrenal gland. Fundamental Applied Toxicology. 1984;4:105–119
  33. Harvey PW. The Adrenal in Toxicology: Target Organ and Modulator of Toxicity. London: Taylor and Francis; 1996;
  34. Raven PW, Hinson JP. Transport, action and metabolism of adrenal hormones and pathology and pharmacology of the adrenal gland. In: The Adrenal in Toxicology: Target Organ and Modulator of Toxicity. London: Taylor and Francis; 1996. p. 53–79.
  35. Gopinath C. Comparative endocrine carcinogenesis. In:  Harvey PW,  Rush KC,  Cockburn A editor. Endocrine and Hormonal Toxicology. Chichester: Wiley; 1999;p. 155–167
  36. Clevenger CV, Furth PA, Hankinson SE, Schuler LA. The role of prolactin in mammary carcinoma. Endocrine Reviews. 2003;24:1–27
  37. Tworoger SS, Eliassen AH, Rosner B, et al. Plasma prolactin concentrations and risk of postmenopausal breast cancer. Cancer Research. 2004;64:6814–6819
  38. Perks CM, Keith AJ, Goodhew KL, et al. Prolactin acts as a potent survival factor for human breast cancer cell lines. British Journal of Cancer. 2004;91:305–311
  39. Meng J, Tsai-Morris CH, Dufau ML. Human prolactin receptor variants in breast cancer: low ratio of short forms to the long form human prolactin receptor associated with mammary carcinoma. Cancer Research. 2004;64:5677–5682
  40. Gutzman JH, Rugowski DE, Schroeder MD, et al. Multiple kinase cascades mediate prolactin signals to activate protein-1 in breast cancer cells. Molecular Endocrinology. 2004;18:3064–3075
  41. USEPA. Determination of the appropriate FQPA safety factors for use in the tolerance setting process. Office of Pesticide Programs, Office of Prevention, Pesticides and Toxic Substances. http://www.epa.gov/oppfead1/trac/science/#10_fold; 2002.
  42. Kimmel CA, King MD, Makris SL. Risk assessment perspectives for developmental immunotoxicology. In:  Holladay SD editors. Developmental Immunotoxicology. Boca Raton: CRC Press; 2005;p. 45–63
  43. Holladay SD. Developmental Immunotoxicology. Boca Raton: CRC Press; 2005;
  44. Philip JC, John CD, Gillies GE, Buckingham JC. Neuroendocrine and pituitary toxicology: targets for drug action and potential consequences on immune function. In:  Harvey PW,  Rush KC,  Cockburn A editor. Endocrine and Hormonal Toxicology. Chichester: Wiley; 1999;p. 171–208
  45. Spinedi E, Perez NB, Gaillard RC. Neuroendocrine–immune interaction: impact of gender, negative energetic balance condition, and developmental stage on the mechanisms of the acute phase response of the inflammatory process in mammals. In:  Holladay SD editors. Developmental Immunotoxicology. Boca Raton: CRC Press; 2005;p. 303–353
  46. Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocrine Reviews. 1984;5:25–44
  47. Johnson I, Harvey PW. Study on the scientific evaluation of 12 substances in the context of endocrine disrupter priority list of actions. Report for the European Commission, Environment Directorate General, 2002, 613 pp. Available at http://europa.eu.int/comm/environment/endocrine/documents/wrc_report.pdf; 2002.
  48. Routledge EJ, Parker J, Odum J, et al. Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. Toxicology and Applied Pharmacology. 1998;153:12–19
  49. Byford JR, Shaw LE, Drew MG, et al. Oestrogenic activity of parabens in MCF7 human breast cancer cells. The Journal of Steroid Biochemistry and Molecular Biology. 2002;80:49–60
  50. Lemini C, Jaimez R, Avila ME, et al. In vivo and in vitro estrogen bioactivities of alkyl parabens. Toxicology and Industrial Health. 2003;19:69–79
  51. Hossaini A, Larsen JJ, Larsen JC. Lack of oestrogenic effects of food preservatives (parabens) in uterotrophic assays. Food and Chemical Toxicology. 2000;38:319–323
  52. Oishi S. Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Food and Chemical Toxicology. 2004;42:1845–1849
  53. Okubo T, Yokoyama Y, Kano K, Kano I. ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ER alpha and PR. Food and Chemical Toxicology. 2001;39:1225–1232
  54. Oishi S. Effects of propylparaben on the male reproductive system. Food and Chemical Toxicology. 2002;40:1807–1813
  55. Daston GP. Developmental toxicity evaluation of butylparaben in Sprague–Dawley rats. Birth Defects Research Part B Developmental and Reproductive Toxicology. 2004;71:296–302
  56. Oishi S. Effects of butylparaben on the male reproductive system in rats. Toxicology and Industrial Health. 2001;17:31–39
  57. Oishi S. Effects of butylparaben on the male reproductive system in mice. Archives of Toxicology. 2002;76:423–429
  58. Kang KS, Che JH, Ryu DY, et al. Decreased sperm number and motile activity on the F1 offspring maternally exposed to butyl p-hydroxybenzoic acid (butyl paraben). The Journal of Veterinary Medical Science. 2002;64:227–235
  59. Darbre PD, Byford JR, Shaw LE, et al. Oestrogenic activity of isobutylparaben in vitro and in vivo. Journal of Applied Toxicology. 2002;22:219–226
  60. Darbre PD, Byford JR, Shaw LE, et al. Oestrogenic activity of benzylparaben. Journal of Applied Toxicology. 2003;23:43–51
  61. Lemini C, Silva G, Timossi C, et al. Estrogenic effects of p-hydroxybenzoic acid in CD1 mice. Environmental Research. 1997;75:130–134
  62. Bando H, Mohri S, Yamashita F, et al. Effects of skin metabolism on percutaneous penetration of lipophilic drugs. Journal of Pharmaceutical Sciences. 1997;86:759–761
  63. Darbre PD, Aljarrah A, Miller WR, et al. Concentrations of parabens in human breast tumours. Journal of Applied Toxicology. 2004;24:5–13
  64. Harvey PW, Everett DJ. Significance of the detection of esters of p-hydroxybenzoic acid (parabens) in human breast tumours. Journal of Applied Toxicology. 2004;24:1–4
  65. Clarke R, Leonessa F, Welch JN, Skaar TC. Cellular and molecular pharmacology of antiestrogen action and resistance. Pharmacological Reviews. 2001;53:25–72
  66. SCF. Statement of the Scientific Committee on Food on the Parabens. European Commission, Health and Consumer Protection Directorate, Scientific Committee on Food SCF/CS/ADD/CONS/53 Final 2 April 2003. http://europa.eu.int/comm/food/fs/sc/scf; 2003.
  67. Willis L. Final report on the safety assessment of isobutylparaben and isopropylparaben. Journal of the American College of Toxicology. 1995;14:364–372
  68. McGrath KG. An earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving. European Journal of Cancer Prevention. 2003;12:479–485
  69. Mirick DK, Davis S, Thomas DB. Antiperspirant use and the risk of breast cancer. Journal of the National Cancer Institute. 2002;94(20):1578–1580
  70. Bradford-Hill A. The environment and disease: association or causation. Proceedings of the Royal Society of Medicine. 1966;58:295
  71. Luu HMD, Hutter JC. Bioavailability of octamethylcyclotetrasiloxane (D4) after exposure to silicones by inhalation and implantation. Environmental Health Perspectives. 2001;109:1095–1101
  72. Zareba G, Galein R, Morrow PE, Utell MJ. Percutaneous absorption studies of octamethylcyclotetrasiloxane using the human skin/nude mouse model. Skin Pharmacology and Applied Skin Physiology. 2002;15:184–194
  73. Kala SV, Lykissa ED, Neely MW, Lieberman MW. Low molecular weight silicones are widely distributed after a single subcutaneous injection in mice. The American Journal of Pathology. 1998;152:645–649
  74. He B, Rhodes-Brower S, Miller MR, et al. Octamethylcyclotetrasiloxane exhibits estrogenic activity in mice via ER alpha. Toxicology and Applied Pharmacology. 2003;192:254–261
  75. McKim JM, Wilga PC, Breslin WJ, et al. Potential estrogenic and antiestrogenic activity of the cyclic siloxane octamethylcyclotetrasiloxane (D4) and the linear siloxane hexamethyldisiloxane (HMDS) in immature rats using the uterotrophic assay. Toxicological Sciences. 2001;63:37–46
  76. Darbre PD. Underarm cosmetics are a cause of breast cancer. European Journal of Cancer Prevention. 2001;10:389–393
  77. Darbre PD. Underarm cosmetics and breast cancer. Journal of Applied Toxicology. 2003;23:89–95
  78. EFSA . Opinion of the scientific panel on food additives, flavouring, processing aids and materials in contact with food on a request from the commission related to para hydroxybenzoates (E 214-219). Question number EFSA-Q-2004-063.. The EFSA Journal. 2004;83:1–26
  79. Ricci PF, Cox LA, MacDonald TR. Precautionary principles: a jurisdiction-free framework for decision making under risk. Human Experimental Toxicology. 2004;23:579–600
  80. Ellman LM, Sunstein CR. Hormesis, the precautionary principle and legal regulation. Human Experimental Toxicology. 2004;23:601–611
  81. Hofer T, Gerner I, Gundert-Remy U, et al. Animal testing and alternative approaches for the human health risk assessment under the proposed new European regulation. Archives of Toxicology. 2004;78:549–564
  82. Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract?. Lancet. 1993;341:1392–1395
  83. Beral V. Million women study collaborators. Breast cancer and hormone replacement in the million women study. Lancet. 2003;362:419–427
  84. Ellsworth DL, Ellswoth RE, Love B, et al. Outer breast quadrants demonstrate increased levels of genomic instability. Annals of Surgical Oncology. 2004;11:861–868
  85. Ellsworth DL, Ellsworth RE, Liebman MN, et al. Genomic instability in histologically normal breast tissues: implications for carcinogenesis. Lancet Oncology. 2004;5:753–758
  86. Harvey PW. Human relevance of rodent prolactin-induced non-genotoxic mammary carcinogenesis: prolactin involvement in human breast cancer and significance for toxicology risk assessments. Journal of Applied Toxicology. 2005;25:179–183
  87. Gikas PD, Mansfield L, Mokbel K. Do underarm cosmetics cause breast cancer?. International Journal of Fertility. 2004;49:212–214
  88. Loretz LJ, Api AM, Barraj LM, et al. Exposure data for cosmetic products: lipstick, body lotion, and face cream. Food and Chemical Toxicology. 2005;43:279–291

PII: S1521-690X(05)00075-8

doi: 10.1016/j.beem.2005.09.008

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 20, Issue 1 , Pages 145-165 , March 2006

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