Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 1995 Apr;103(4):346–351. doi: 10.1289/ehp.95103346

Environmental and dietary estrogens and human health: is there a problem?

S H Safe 1
PMCID: PMC1519094  PMID: 7607134

Abstract

It has been hypothesized that organochlorine pesticides and other environmental and dietary estrogens may be associated with the increased incidence of breast cancer in women and decreased sperm concentrations and reproductive problems in men. However, elevation of organochlorine compounds such as dichlorodipehenyldichloroethylene (DDE) and polychlorinated biphenyls (PCBs) in breast cancer patients is not consistently observed. Reanalysis of the data showing that male sperm counts decreased by over 40% during 1940 to 1990 indicated that inadequate statistical methods were used and that the data did not support a significant decline in sperm count. Humans are exposed to both natural and industrial chemicals which exhibit estrogenic and antiestrogenic activities. For example, bioflavonoids, which are widely distributed in foods, and several industrial compounds, including organochlorine pesticides and various phenolic chemicals, exhibit estrogenic activity. Humans are also exposed to chemicals which inhibit estrogen-induced responses such as the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chlorinated aromatics, polynuclear aromatic hydrocarbon combustion products, and indole-3-carbinol, which is found in cruciferous vegetables. Many of the weak estrogenic compounds, including bioflavonoids, are also antiestrogenic at some concentrations. A mass balance of dietary levels of industrial and natural estrogens, coupled with their estimated estrogenic potencies, indicates that the dietary contribution of estrogenic industrial compounds is 0.0000025% of the daily intake of estrogenic flavonoids in the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
347

Images in this article

346p346-a
on p.346
348Figure 1.
on p.348
348Figure 2.
on p.348

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adlercreutz H., Markkanen H., Watanabe S. Plasma concentrations of phyto-oestrogens in Japanese men. Lancet. 1993 Nov 13;342(8881):1209–1210. doi: 10.1016/0140-6736(93)92188-y. [DOI] [PubMed] [Google Scholar]
  2. Astroff B., Rowlands C., Dickerson R., Safe S. 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibition of 17 beta-estradiol-induced increases in rat uterine epidermal growth factor receptor binding activity and gene expression. Mol Cell Endocrinol. 1990 Sep 10;72(3):247–252. doi: 10.1016/0303-7207(90)90149-3. [DOI] [PubMed] [Google Scholar]
  3. Astroff B., Safe S. 2,3,7,8-Tetrachlorodibenzo-p-dioxin as an antiestrogen: effect on rat uterine peroxidase activity. Biochem Pharmacol. 1990 Feb 1;39(3):485–488. doi: 10.1016/0006-2952(90)90054-o. [DOI] [PubMed] [Google Scholar]
  4. Auger J., Kunstmann J. M., Czyglik F., Jouannet P. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med. 1995 Feb 2;332(5):281–285. doi: 10.1056/NEJM199502023320501. [DOI] [PubMed] [Google Scholar]
  5. Bergman A., Klasson-Wehler E., Kuroki H. Selective retention of hydroxylated PCB metabolites in blood. Environ Health Perspect. 1994 May;102(5):464–469. doi: 10.1289/ehp.94102464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bertazzi A., Pesatori A. C., Consonni D., Tironi A., Landi M. T., Zocchetti C. Cancer incidence in a population accidentally exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin. Epidemiology. 1993 Sep;4(5):398–406. doi: 10.1097/00001648-199309000-00004. [DOI] [PubMed] [Google Scholar]
  7. Berthois Y., Katzenellenbogen J. A., Katzenellenbogen B. S. Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2496–2500. doi: 10.1073/pnas.83.8.2496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Biegel L., Safe S. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cell growth and the secretion of the estrogen-induced 34-, 52- and 160-kDa proteins in human breast cancer cells. J Steroid Biochem Mol Biol. 1990 Dec 10;37(5):725–732. doi: 10.1016/0960-0760(90)90357-q. [DOI] [PubMed] [Google Scholar]
  9. Bitman J., Cecil H. C. Estrogenic activity of DDT analogs and polychlorinated biphenyls. J Agric Food Chem. 1970 Nov-Dec;18(6):1108–1112. doi: 10.1021/jf60172a019. [DOI] [PubMed] [Google Scholar]
  10. Bitman J., Cecil H. C., Harris S. J., Fries G. F. Estrogenic activity of o,p'-DDT in the mammalian uterus and avian oviduct. Science. 1968 Oct 18;162(3851):371–372. doi: 10.1126/science.162.3851.371. [DOI] [PubMed] [Google Scholar]
  11. Bromwich P., Cohen J., Stewart I., Walker A. Decline in sperm counts: an artefact of changed reference range of "normal"? BMJ. 1994 Jul 2;309(6946):19–22. doi: 10.1136/bmj.309.6946.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Brown D. P. Mortality of workers exposed to polychlorinated biphenyls--an update. Arch Environ Health. 1987 Nov-Dec;42(6):333–339. doi: 10.1080/00039896.1987.9934355. [DOI] [PubMed] [Google Scholar]
  13. Carlsen E., Giwercman A., Keiding N., Skakkebaek N. E. Evidence for decreasing quality of semen during past 50 years. BMJ. 1992 Sep 12;305(6854):609–613. doi: 10.1136/bmj.305.6854.609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chaloupka K., Krishnan V., Safe S. Polynuclear aromatic hydrocarbon carcinogens as antiestrogens in MCF-7 human breast cancer cells: role of the Ah receptor. Carcinogenesis. 1992 Dec;13(12):2233–2239. doi: 10.1093/carcin/13.12.2233. [DOI] [PubMed] [Google Scholar]
  15. Colborn T., vom Saal F. S., Soto A. M. Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect. 1993 Oct;101(5):378–384. doi: 10.1289/ehp.93101378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Davis D. L., Bradlow H. L., Wolff M., Woodruff T., Hoel D. G., Anton-Culver H. Medical hypothesis: xenoestrogens as preventable causes of breast cancer. Environ Health Perspect. 1993 Oct;101(5):372–377. doi: 10.1289/ehp.93101372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. DeVito M. J., Thomas T., Martin E., Umbreit T. H., Gallo M. A. Antiestrogenic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin: tissue-specific regulation of estrogen receptor in CD1 mice. Toxicol Appl Pharmacol. 1992 Apr;113(2):284–292. doi: 10.1016/0041-008x(92)90126-d. [DOI] [PubMed] [Google Scholar]
  18. Dewailly E., Dodin S., Verreault R., Ayotte P., Sauvé L., Morin J., Brisson J. High organochlorine body burden in women with estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1994 Feb 2;86(3):232–234. doi: 10.1093/jnci/86.3.232. [DOI] [PubMed] [Google Scholar]
  19. Ecobichon D. J., MacKenzie D. O. The uterotropic activity of commercial and isomerically-pure chlorobiphenyls in the rat. Res Commun Chem Pathol Pharmacol. 1974 Sep;9(1):85–95. [PubMed] [Google Scholar]
  20. Falck F., Jr, Ricci A., Jr, Wolff M. S., Godbold J., Deckers P. Pesticides and polychlorinated biphenyl residues in human breast lipids and their relation to breast cancer. Arch Environ Health. 1992 Mar-Apr;47(2):143–146. [PubMed] [Google Scholar]
  21. Gallo M. A., Hesse E. J., Macdonald G. J., Umbreit T. H. Interactive effects of estradiol and 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic cytochrome P-450 and mouse uterus. Toxicol Lett. 1986 Jul-Aug;32(1-2):123–132. doi: 10.1016/0378-4274(86)90058-5. [DOI] [PubMed] [Google Scholar]
  22. Gierthy J. F., Bennett J. A., Bradley L. M., Cutler D. S. Correlation of in vitro and in vivo growth suppression of MCF-7 human breast cancer by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cancer Res. 1993 Jul 1;53(13):3149–3153. [PubMed] [Google Scholar]
  23. Gierthy J. F., Lincoln D. W., 2nd Inhibition of postconfluent focus production in cultures of MCF-7 human breast cancer cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Breast Cancer Res Treat. 1988 Oct;12(2):227–233. doi: 10.1007/BF01805943. [DOI] [PubMed] [Google Scholar]
  24. Gierthy J. F., Lincoln D. W., Gillespie M. B., Seeger J. I., Martinez H. L., Dickerman H. W., Kumar S. A. Suppression of estrogen-regulated extracellular tissue plasminogen activator activity of MCF-7 cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cancer Res. 1987 Dec 1;47(23):6198–6203. [PubMed] [Google Scholar]
  25. Hammond B., Katzenellenbogen B. S., Krauthammer N., McConnell J. Estrogenic activity of the insecticide chlordecone (Kepone) and interaction with uterine estrogen receptors. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6641–6645. doi: 10.1073/pnas.76.12.6641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Harper N., Wang X., Liu H., Safe S. Inhibition of estrogen-induced progesterone receptor in MCF-7 human breast cancer cells by aryl hydrocarbon (Ah) receptor agonists. Mol Cell Endocrinol. 1994 Aug;104(1):47–55. doi: 10.1016/0303-7207(94)90050-7. [DOI] [PubMed] [Google Scholar]
  27. Holcomb M., Safe S. Inhibition of 7,12-dimethylbenzanthracene-induced rat mammary tumor growth by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Cancer Lett. 1994 Jul 15;82(1):43–47. doi: 10.1016/0304-3835(94)90144-9. [DOI] [PubMed] [Google Scholar]
  28. Hunter D. J., Kelsey K. T. Pesticide residues and breast cancer: the harvest of a silent spring? J Natl Cancer Inst. 1993 Apr 21;85(8):598–599. doi: 10.1093/jnci/85.8.598. [DOI] [PubMed] [Google Scholar]
  29. Key T., Reeves G. Organochlorines in the environment and breast cancer. BMJ. 1994 Jun 11;308(6943):1520–1521. doi: 10.1136/bmj.308.6943.1520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kociba R. J., Keyes D. G., Beyer J. E., Carreon R. M., Wade C. E., Dittenber D. A., Kalnins R. P., Frauson L. E., Park C. N., Barnard S. D. Results of a two-year chronic toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. Toxicol Appl Pharmacol. 1978 Nov;46(2):279–303. doi: 10.1016/0041-008x(78)90075-3. [DOI] [PubMed] [Google Scholar]
  31. Korach K. S., Sarver P., Chae K., McLachlan J. A., McKinney J. D. Estrogen receptor-binding activity of polychlorinated hydroxybiphenyls: conformationally restricted structural probes. Mol Pharmacol. 1988 Jan;33(1):120–126. [PubMed] [Google Scholar]
  32. Krieger N., Wolff M. S., Hiatt R. A., Rivera M., Vogelman J., Orentreich N. Breast cancer and serum organochlorines: a prospective study among white, black, and Asian women. J Natl Cancer Inst. 1994 Apr 20;86(8):589–599. doi: 10.1093/jnci/86.8.589. [DOI] [PubMed] [Google Scholar]
  33. Krishnan A. V., Stathis P., Permuth S. F., Tokes L., Feldman D. Bisphenol-A: an estrogenic substance is released from polycarbonate flasks during autoclaving. Endocrinology. 1993 Jun;132(6):2279–2286. doi: 10.1210/endo.132.6.8504731. [DOI] [PubMed] [Google Scholar]
  34. Krishnan V., Safe S. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs) as antiestrogens in MCF-7 human breast cancer cells: quantitative structure-activity relationships. Toxicol Appl Pharmacol. 1993 May;120(1):55–61. doi: 10.1006/taap.1993.1086. [DOI] [PubMed] [Google Scholar]
  35. Kühnau J. The flavonoids. A class of semi-essential food components: their role in human nutrition. World Rev Nutr Diet. 1976;24:117–191. [PubMed] [Google Scholar]
  36. Liu H., Wormke M., Safe S. H., Bjeldanes L. F. Indolo[3,2-b]carbazole: a dietary-derived factor that exhibits both antiestrogenic and estrogenic activity. J Natl Cancer Inst. 1994 Dec 7;86(23):1758–1765. doi: 10.1093/jnci/86.23.1758. [DOI] [PubMed] [Google Scholar]
  37. MacLeod J., Wang Y. Male fertility potential in terms of semen quality: a review of the past, a study of the present. Fertil Steril. 1979 Feb;31(2):103–116. doi: 10.1016/s0015-0282(16)43808-2. [DOI] [PubMed] [Google Scholar]
  38. Makela S, Davis VL, Tally WC, Korkman J, Salo L, Vihko R, Santti R, Korach KS. Dietary Estrogens Act through Estrogen Receptor-Mediated Processes and Show No Antiestrogenicity in Cultured Breast Cancer Cells. Environ Health Perspect. 1994 Jun;102(6-7):572–578. doi: 10.1289/ehp.94102572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Markaverich B. M., Roberts R. R., Alejandro M. A., Johnson G. A., Middleditch B. S., Clark J. H. Bioflavonoid interaction with rat uterine type II binding sites and cell growth inhibition. J Steroid Biochem. 1988;30(1-6):71–78. doi: 10.1016/0022-4731(88)90078-7. [DOI] [PubMed] [Google Scholar]
  40. Messina M. J., Persky V., Setchell K. D., Barnes S. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr Cancer. 1994;21(2):113–131. doi: 10.1080/01635589409514310. [DOI] [PubMed] [Google Scholar]
  41. Miksicek R. J. Commonly occurring plant flavonoids have estrogenic activity. Mol Pharmacol. 1993 Jul;44(1):37–43. [PubMed] [Google Scholar]
  42. Mussalo-Rauhamaa H., Häsänen E., Pyysalo H., Antervo K., Kauppila R., Pantzar P. Occurrence of beta-hexachlorocyclohexane in breast cancer patients. Cancer. 1990 Nov 15;66(10):2124–2128. doi: 10.1002/1097-0142(19901115)66:10<2124::aid-cncr2820661014>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  43. Robinson P. E., Mack G. A., Remmers J., Levy R., Mohadjer L. Trends of PCB, hexachlorobenzene, and beta-benzene hexachloride levels in the adipose tissue of the U.S. population. Environ Res. 1990 Dec;53(2):175–192. doi: 10.1016/s0013-9351(05)80118-5. [DOI] [PubMed] [Google Scholar]
  44. Robison A. K., Mukku V. R., Spalding D. M., Stancel G. M. The estrogenic activity of DDT: the in vitro induction of an estrogen-inducible protein by o,p'-DDT. Toxicol Appl Pharmacol. 1984 Dec;76(3):537–543. doi: 10.1016/0041-008x(84)90358-2. [DOI] [PubMed] [Google Scholar]
  45. Safe S., Astroff B., Harris M., Zacharewski T., Dickerson R., Romkes M., Biegel L. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds as antioestrogens: characterization and mechanism of action. Pharmacol Toxicol. 1991 Dec;69(6):400–409. doi: 10.1111/j.1600-0773.1991.tb01321.x. [DOI] [PubMed] [Google Scholar]
  46. Safe S. Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). Crit Rev Toxicol. 1990;21(1):51–88. doi: 10.3109/10408449009089873. [DOI] [PubMed] [Google Scholar]
  47. Sharpe R. M., Skakkebaek N. E. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet. 1993 May 29;341(8857):1392–1395. doi: 10.1016/0140-6736(93)90953-e. [DOI] [PubMed] [Google Scholar]
  48. Soto A. M., Chung K. L., Sonnenschein C. The pesticides endosulfan, toxaphene, and dieldrin have estrogenic effects on human estrogen-sensitive cells. Environ Health Perspect. 1994 Apr;102(4):380–383. doi: 10.1289/ehp.94102380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Soto A. M., Justicia H., Wray J. W., Sonnenschein C. p-Nonyl-phenol: an estrogenic xenobiotic released from "modified" polystyrene. Environ Health Perspect. 1991 May;92:167–173. doi: 10.1289/ehp.9192167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Stillman R. J. In utero exposure to diethylstilbestrol: adverse effects on the reproductive tract and reproductive performance and male and female offspring. Am J Obstet Gynecol. 1982 Apr 1;142(7):905–921. doi: 10.1016/s0002-9378(16)32540-6. [DOI] [PubMed] [Google Scholar]
  51. Stoewsand G. S., Anderson J. L., Munson L. Protective effect of dietary brussels sprouts against mammary carcinogenesis in Sprague-Dawley rats. Cancer Lett. 1988 Mar;39(2):199–207. doi: 10.1016/0304-3835(88)90105-x. [DOI] [PubMed] [Google Scholar]
  52. Stone R. Environmental estrogens stir debate. Science. 1994 Jul 15;265(5170):308–310. doi: 10.1126/science.8023147. [DOI] [PubMed] [Google Scholar]
  53. TULLNER W. W. Uterotrophic action of the insecticide methoxychlor. Science. 1961 Mar 3;133(3453):647–647. doi: 10.1126/science.133.3453.647. [DOI] [PubMed] [Google Scholar]
  54. Tiwari R. K., Guo L., Bradlow H. L., Telang N. T., Osborne M. P. Selective responsiveness of human breast cancer cells to indole-3-carbinol, a chemopreventive agent. J Natl Cancer Inst. 1994 Jan 19;86(2):126–131. doi: 10.1093/jnci/86.2.126. [DOI] [PubMed] [Google Scholar]
  55. Unger M., Kiaer H., Blichert-Toft M., Olsen J., Clausen J. Organochlorine compounds in human breast fat from deceased with and without breast cancer and in a biopsy material from newly diagnosed patients undergoing breast surgery. Environ Res. 1984 Jun;34(1):24–28. doi: 10.1016/0013-9351(84)90072-0. [DOI] [PubMed] [Google Scholar]
  56. Verma A. K., Johnson J. A., Gould M. N., Tanner M. A. Inhibition of 7,12-dimethylbenz(a)anthracene- and N-nitrosomethylurea-induced rat mammary cancer by dietary flavonol quercetin. Cancer Res. 1988 Oct 15;48(20):5754–5758. [PubMed] [Google Scholar]
  57. Welch R. M., Levin W., Conney A. H. Estrogenic action of DDT and its analogs. Toxicol Appl Pharmacol. 1969 Mar;14(2):358–367. doi: 10.1016/0041-008x(69)90117-3. [DOI] [PubMed] [Google Scholar]
  58. White R., Jobling S., Hoare S. A., Sumpter J. P., Parker M. G. Environmentally persistent alkylphenolic compounds are estrogenic. Endocrinology. 1994 Jul;135(1):175–182. doi: 10.1210/endo.135.1.8013351. [DOI] [PubMed] [Google Scholar]
  59. Winter C. K. Dietary pesticide risk assessment. Rev Environ Contam Toxicol. 1992;127:23–67. doi: 10.1007/978-1-4613-9751-9_2. [DOI] [PubMed] [Google Scholar]
  60. Wolff M. S., Toniolo P. G., Lee E. W., Rivera M., Dubin N. Blood levels of organochlorine residues and risk of breast cancer. J Natl Cancer Inst. 1993 Apr 21;85(8):648–652. doi: 10.1093/jnci/85.8.648. [DOI] [PubMed] [Google Scholar]
  61. Zacharewski T. R., Bondy K. L., McDonell P., Wu Z. F. Antiestrogenic effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on 17 beta-estradiol-induced pS2 expression. Cancer Res. 1994 May 15;54(10):2707–2713. [PubMed] [Google Scholar]
  62. el-Bayoumy K. Environmental carcinogens that may be involved in human breast cancer etiology. Chem Res Toxicol. 1992 Sep-Oct;5(5):585–590. doi: 10.1021/tx00029a001. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES