How strong is the evidence of a link between environmental chemicals and adverse effects on human reproductive health?BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.328.7437.447 (Published 19 February 2004) Cite this as: BMJ 2004;328:447
- Extended explanation for:
(Figure 1) The three potential pathways via which "endocrine disrupting" environmental chemicals have the potential to affect the actions of sex steroid hormones in humans.1 Because the actions of any such chemicals occur via modulation of normal, physiological mechanisms, manifestation of any effects will be similar to a hormonal disorder arising because of lifestyle or genetic influences. As a result, proof that such chemicals do, or do not, exert effects in humans is complex.
- Many common environmental chemicals have intrinsically (weak) oestrogenic activity and therefore have the potential to interact with oestrogen receptors as weak oestrogen receptor agonists; examples are some organochlorine chemicals, bisphenolic and alkylphenolic compounds.1
- A small number of chemicals may have weak androgenic activity and therefore have the potential to interact with androgen receptors as androgen receptor agonists—for example, compounds in paper mill effluents.
- Several pesticides or fungicides (for example, DDT metabolites, vinclozolin, linuron) are androgen receptor antagonists and therefore have the potential to block the actions of endogenous androgens; this would be most important during sexual differentiation of the male fetus.
- Some chemicals may be weak oestrogen receptor antagonists with the potential to interfere with actions of endogenous oestrogens, either via binding to oestrogen receptors or via other mechanisms; examples are some PCBs, dioxin-like compounds.1
- Some ubiquitous environmental chemicals have the potential to alter production or metabolism of endogenous androgens and oestrogens, thus altering their bioavailability and actions; examples are shown in the diagram.1 5, 16, 17
(Figure 2) Cancer of the testis and female breast is becoming commoner in most registries which have been examined.8 Registry based data suggesting changes in congenital malformations of the male genital tract (cryptorchidism, hypospadias,w23 are less robust, and confounded by ascertainment and reporting biases.w23-w25 Evidence that sperm counts are falling is most controversial, although a recent review concluded that downward trends in Europe and the United States were not explained by any known confounding factors.w26 Testicular cancer, cryptorchidsim, hypospadias, and defects of spermatogenesis may be facets of one clinical problem—testicular dysgenesis sysndrome.10 16
(Figure 3) A pregnant woman is used in the illustration to emphasise the potential for transfer of such chemicals to the fetusw17-w20 and perhaps for them to accumulate in amniotic fluid.  If such chemicals exert effects on the fetus, these may not manifest as disease until adulthood, making establishment of cause and effect an almost impossible task in the case of non-accumulative chemicals.w5 w8 For some chemicals, especially for organochlorine chemicals, there may be bioaccumulation in body fat,w21 w22 such as in the breast.1 12 Such chemicals may be delivered to the baby by breast feedingw18 or may remain for decades in the breast tissue of nulliparous women or in those who choose not to breastfeed their baby. Because such chemicals are long lived, measuring them may provide an index of a woman’s relative exposure earlier in life (including during pregnancy), and such measurements have been used to show relationships to reproductive changes in the offspring (see text). Such studies are not possible for chemicals with short half-lives in the body, such as phthalates. Chemicals such as phthalates may be present in cosmetics, deodorants, etc by design or as the result of contamination. Also, chemical exposures are likely to be lifestyle-dependent (for example, if the mother smokes), and diet and lifestyle can have important effects on the developing fetus.17w15
w1Nakai K, Satoh H. Developmental neurotoxicity following prenatal exposures to methylmercury and PCBs in humans from epidemiological studies. Tohoku J Exp Med 2002, 196: 89-98
w2Pesatori AC, Consonni D, Bachetti S, Zocchetti C, Bonzini M, Baccarelli A, Bertazzi PA. Short- and long-term morbidity and mortality in the population exposed to dioxin after the "Seveso accident". Ind Health 2003, 41: 127-138
w3Dhara VR, Dhara R. The Union Carbide disaster in Bhopal: a review of health effects. Arch Environ Health 2002, 57: 391-404
w4Environmental Working Group (Houlihan J, Brody C, Schwan B). Not too pretty: phthalates, beauty products and the FDA. [Online: http://www.ewg.org/pub/home/reports/beautysecrets/chap3.html] 2003
w5Toppari J, Larsen JC, Christiansen P, Giwercman A, Grandjean P, Guillette LJ Jr, Jégou B, Jensen TK, Jouannet P, Keiding N, Leffers H, McLachlan JA, Meyer O, Müller J, Rajpert-De Meyts E, Scheike T, Sharpe RM, Sumpter JS, Skakkebaek NE. Male reproductive health and environmental xenoestrogens. Environ Health Perspect 1996, 104 (Suppl 4): 741-803
w6Wolff MS, Berkowitz GS, Brower S, Senie R, Bleiweiss IJ, Tarter P, Pace B, Roy N, Wallenstein S, Weston A. Organochlorine exposures and breast cancer risk in New York city women. Environ Res 2000, 84: 151-161
w7Darbre PD. Review: Underarm cosmetics and breast cancer. J Appl Toxicol 2003, 23: 89-95
w8Birnbaum LS, Fenton SE. Cancer and developmental exposure to endocrine disruptors. Environ Health Perspect 2003, 111: 389-394
w9Vrijheid M, Armstrong B, Dolk H, van Tongeren M, Botting B. Risk of hypospadias in relation to maternal occupational exposure to potential endocrine disrupting chemicals. Occup Environ Med 2003, 60: 543-550
w10Kester MH, Bulduck S, Tibboel D, Meinl W, Glatt H, Falany CN, Coughtrie MW, Bergman A, Safe SH, Kuiper GG, Schuur AG, Brouwer A, Visser TJ. Potent inhibition of estrogen sulfotransferase by hydroxylated PCB metabolites: a novel pathway explaining the estrogenic activity of PCBs. Endocrinology 2000, 141: 1897-1900
w11Kester MH, Bulduck S, van Toor H, Tibboel D, Meinl W, Glatt H, Falany CN, Coughtrie MW, Schuur AG, Brouwer A, Visser TJ. Potent inhibition of estrogen sulfotransferase by hydroxylated metabolites of polyhalogenated hydrocarbons reveals alternative mechanism for estrogenic activity of endocrine disrupters. J Clin Endocrinol Metab 2002, 87: 1142-1150
w12Zheng W, Xie D, Cerhan JR, Sellers TA, Wen W, Folsom AR. Sulfotransferase 1A1 polymorphism, endogenous estrogen exposure, well-done meat intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2001, 10: 89-94
W13Swan SH, Brazil C, Drobnis EZ, Liu F, Kruse RL, Hatch M, Redmon JB, Wang C, Overstreet JW, and the study for future families research group. Geographic differences in semen quality of fertile U.S. males. Environ Health Perspect 2003, 111: 414-420
w14Evans SM, Nicholson GJ. The use of imposex to assess tributyltin contamination in coastal waters and open seas. Sci Total Environ 2000, 258: 73-80
w15O’Brien PMS, Wheeler T, Barker DJP (Editors). Fetal programming: influences on development and disease in later life. Royal College of Obstetricians & Gynaecologists Press, London 1999
w16Guvenius DM, Aronsson A, Ekman-Ordeberg G, Bergman A, Noren K. Human prenatal and postnatal exposure to polybrominated diphenyl ethers, polychlorinated biphenyls, polychlorobiphenylols, and pentachlorophenol. Environ Health Perspect 2003, 111: 1235-1241
w17Mazdai A, Dodder NG, Abernathy MP, Hites RA, Bigsbay RM. Polybrominated diphenyl ethers in maternal and fetal blood samples. Environ Health Perspect 2003, 111: 1249-1252
w18Brouwer A, Ahlborg UG, van Leeuwen FX, Feeley MM. Report of the WHO working group on the assessment of health risks for human infants from exposure to PCDDs, PCDFs and PCBs. Chemosphere 1998, 37: 1627-1643
w19Ikezuki Y, Tsutsumi O, Takai Y, Kamei Y, Taketani Y. Determination of bishenol A concentrations in human biological fluids reveals significant early prenatal exposure. Hum Reprod 2002, 17: 2839-2841
w20Siddiqui M, Srivastva S, Srivastava S, Mehrotra N, Mathur N, Tandon I. Persistent chlorinated pesticides and intra-uterine foetal growth retardation: a possible association. Int Arch Occup Environ Health 2003, 76: 75-80
w21Pelletier C, Imbeault P, Tremblay A. Energy balance and pollution by organochlorines and polychlorinated biphenyls. Obesity Rev 2003 4: 17-24
w22Schildkraut J, Denmark-Wahnefried W, De Voto E, Hughes C, Laseter JL, Newman B. Environmental contaminants and body fat distribution. Cancer Epidemiol Biom Prev 1999, 8: 179-183
W23Paulozzi LJ. International trends in rates of hypospadias and cryptorchidism. Environ Health Perspect 1999, 107: 297-302
W24Toppari J, Kaleva M, Virtainen HE. Trends in the incidence of cryptorchidism and hypospadias and methodological limitations of registry-based data. Hum Reprod Update 2001 7: 282-286.
W25Pierik FH, Burdoff A, Rien Nijman JM, de Muinck Keizer-Schrama SM, Juttmann RE, Weber RFA. A high hypospadias rate in The Netherlands. Hum Reprod 2002 17: 1112-1115
W26Swan SH, Elkin EP, Fenster L. The question of declining sperm density revisited: an analysis of 101 studies published 1934-1996. Environ Health Perspect 2000, 108: 961-966
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