How strong is the evidence of a link between environmental chemicals and adverse effects on human reproductive health?
http://www.100md.com
《英国医生杂志》
1 MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH16 4SB
Correspondence to: R M Sharpe r.sharpe@hrsu.mrc.ac.uk
Introduction
Though this article is primarily an overview of the current evidence for reproductive effects resulting from exposure to environmental synthetic chemicals, it is relevant to the debate on wider potential health effects of such exposures. The review was compiled after detailed literature searches and cross referencing and scrutiny of relevant websites on environmental chemicals (see educational resources box). After revising the article in light of reviewers' comments, we sought the opinion of an expert toxicologist in industry to ensure balance in the review.
In this hugely contentious area, polarised opinions predominate (because of the lack of definitive data). There are enormous difficulties in establishing whether exposure to individual chemicals or to chemical mixtures causes harm, as adverse effects may not manifest until many years after exposure (for example, in adulthood after fetal exposure). This difficulty must be factored into any discussion of this topic.
Individuals versus populations, hazard versus risk
An endocrine disruptor is a chemical with the potential to alter hormone action within the body.1 The first endocrine disruptors identified were synthetic chemicals that had weak intrinsic hormonal or anti-hormonal activity, usually oestrogenic or anti-androgenic activity.1 Such compounds, when in the body, have the potential to interact with oestrogen or androgen signalling mechanisms (fig 1). Many ubiquitous environmental chemicals, including organochlorine chemicals, and numerous synthetic chemicals prevalent in developed societies (phenolic compounds, for example) are endocrine disruptors.1 w5 As endocrinology textbooks show, disturbance of hormonal homeostasis can result in clinical problems. However, it remains a topic of heated debate as to whether the potential of endocrine disruptors to disrupt hormone action and cause ill health in humans is a reality or merely a remote, theoretical possibility. What has fuelled this debate has been the increase in incidence of two hormone dependent disorders in humans over the past 70 or more years, namely breast cancer8 and testicular dysgenesis syndrome (comprising low sperm counts, testicular cancer, cryptorchidism, and hypospadias) (fig 2).8-10
Fig 1 Potential pathways of endocrine disruption by environmental chemicals. DDE=1,1-dichloro-2, 2-bis(p-chlorophenyl)ethylene; PAHs=polycyclic aromatic hydrocarbons; PCBs=polychlorinated biphenyls; TBT=tributyltin
Fig 2 Trends in reproductive health, United States (for data sources see bmj.com)
Out of this concern, epidemiological studies were prompted, focusing on exposure to organochlorine chemicals and breast cancer, because many organochlorine chemicals are oestrogenic and, also, they are lipophylic and can accumulate in breast fat. One initial study produced evidence linking organochlorine chemical exposure to increased risk of breast cancer,w6 but most subsequent studies have not confirmed this.11 These have included studies in different countries and those that evaluated exposure to organochlorine chemicals many years before breast cancer developed.11 Although these results are reassuring, doubts remain about whether the most important chemicals were measured,12 w2 whether exposure in the correct age window was evaluated,w9 and what effect mixtures of chemicals may have.13 Present evidence suggests that exposure, as an adult, to organochlorine chemicals alone is not a major determinant of breast cancer. Indeed, it seems intuitively unlikely that endocrine disruptors with weak intrinsic oestrogenic activity1 13 can be as important hormonal players in the aetiology of breast cancer as the woman's own potent endogenous oestrogens.14
For testicular dysgenesis syndrome in males, the aetiological involvement of endocrine disruptors is mainly theoretical.10 Testicular dysgenesis syndrome is thought to arise during early pregnancy. Measuring exposure of the human fetus to chemicals and relating this to disorders that may arise decades later (low sperm counts, testis cancer) has major logistical problems. However, a recent study that reported higher levels of organochlorine chemicals in mothers of men with testicular cancer,15 and new discoveries about phthalates (see below), have reawakened interest in the possible aetiological involvement of environmental chemicals in testicular dysgenesis syndrome.w9
"Trojan horse" environmental chemicals
Though most concern about effects of environmental chemicals has focussed on fetal effects (for example, in testicular dysgenesis syndrome),10 17 w5 recent studies point also to postnatal effects. For example, exposure of boys to endosulfan is associated with delayed puberty, though this could have resulted from prenatal exposure.18 More dramatically, fertile men in an agricultural area of Missouri have been shown to have sperm counts about 40% lower than men in three urban US areas,w13 and to have higher urinary concentrations of three currently used pesticides.19 Similarly, direct measurement of certain phthalate metabolites is significantly related to reduced semen quality in men,20 endometriosis in women,21 and shorter gestation periods in pregnant women.22 Although these new findings are suggestive, for none is the mechanism of the chemical's effect self evident. This leaves doubts as to whether the measured chemicals are the real culprits or are surrogates for other chemical exposures or lifestyle practices.
Warnings from wildlife studies?
Human exposure to environmental synthetic chemicals has changed considerably in the past 70 years. This period has witnessed major changes in our diets, lifestyle, and social practices, some of which may be having profound effects on human health. If environmental chemicals are exerting adverse health effects in humans, these are likely to be small in relation to those caused by our dietary and lifestyle changes, although these factors may interact.w21 w22 Moreover, proving that environmental chemicals do—or do not—cause health problems in humans against this changing background is challenging. Nowhere is this truer than in evaluating the impact of maternal exposures in pregnancy that may affect health of the fetus in later life. This is unquestionably the greatest concern,1 and we believe that alternative precautionary strategies must be adopted, which seek to eliminate or minimise unnecessary risks to the fetus, even in the absence of clear proof of harm. Some of these steps can be taken by individuals—for example, lifestyle changes in women seeking to become pregnant (stopping smoking, reduced use of cosmetics and body creams). Reducing exposures by reducing release of chemicals to the environment, however, requires action by industry and government. The proposals by the Royal Commission on Environmental Pollution as to how this may be achieved (box) seem to be a practical and effective path towards such a goal.
References w1-w26 and extended explanations of the figures are on bmj.com
Contributors: The authors are both employed and paid by the Medical Research Council (MRC) and each heads a research team, focused on the causes of abnormal male reproductive development and function, within the MRC Human Reproductive Sciences Unit. RMS has a longstanding interest in the area of endocrine disruptors and is currently chairman of the UK Society for Endocrinology Expert Group on this topic.
Funding: RMS has received research funding from ECETOC (European Consortium on the Ecotoxicology of Chemicals) and AstraZeneca within the past five years.
Competing interests: RMS and DSI have both received reimbursement of travel expenses for attending meetings sponsored by pharmaceutical companies or the chemical industry.
References
Damstra T, Barlow S, Bergman A, Kavlock R, Van Der Kraak G, eds. Global assessment of the state-of-the-science of endocrine disruptors. International Programme on Chemical Safety, 2002. http://ehp.niehs.nih.gov/who/ (accessed 3 Feb 2004).
Czene K, Lichtenstein P, Hemminki K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family-cancer database. Int J Cancer 2002;99: 260-6.
Jeyaratnam J. Acute pesticide poisoning: a major global health problem. World Health Stat Q 1990;43: 139-44.
Second Health and Nutrition Examination Survey (NHANES). Report on human exposure to environmental chemicals. Atlanta: National Center for Environmental Health, 2003. (Publication No 02-0716.) www.cdc.gov/nceh/dls/report/ (accessed 3 Feb 2003).
Mylchreest E, Sar M, Cattley R, Foster PMD. Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. Toxicol Appl Pharmacol 1999;156: 81-95.
Blount BC, Silva MJ, Caudill SP, Needham LL, Pirkle JL, Sampson EJ, et al. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect 2000;108: 979-82.
Koch HM, Drexler H, Angerer J. An estimation of the daily intake of di (2-ethylhexyl) phthalate (DEHP) and other phthalates in the general population. Int J Hyg Environ Health 2003;206: 1-7.
Surveillance, Epidemiology, and End Results (SEER) Program SEER*Stat Database: Incidence—SEER 9 Regs Public-Use, Nov 2002 Sub (1973-2000), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2003, based on the November 2002 submission. http://seer.cancer.gov/ (accessed 3 Feb 2003).
Huyghe E, Matsuda T, Thonneau P. Increasing incidence of testicular cancer worldwide: a review. J Urol 2003;170: 5-11.
Skakkebaek NE, Rajpert-De Meyts E, Main K. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16: 972-8.
Calle E, Frumkin H, Henley J, Savitz DA, Thun MJ. Organochlorines and breast cancer risk. CA Cancer J Clin 2002;52: 301-9.
N Evans, ed. Environmental health: what is the connection between chemicals and breast cancer. Breast Cancer Fund and Breast Cancer Action, 2003. www.breastcancerfund.org/environment_evidence_main.htm (accessed 3 Feb 2003).
Rajapakse N, Silva E, Kortenkamp A. Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. Env Health Perspect 2002;110: 919-921.
Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 2002;94: 606-16.
Hardell L, van Bavel B, Lindstrom G, Carlberg M, Dreifaldt AC, Wijkstrom H, et al. Increased concentrations of polychlorinated biphenyls, hexachlorobenzene and chlordanes in mothers to men with testicular cancer. Env Health Perspect 2003;111: 930-4.
Fisher JS, Macpherson S, Marchetti N, Sharpe RM. Human `testicular dysgenesis syndrome': a possible model based on in utero exposure of the rat to dibutyl phthalate. Hum Reprod 2003;7: 1383-94.
Sharpe RM, Franks S. Environment, lifestyle and infertility—an inter-generational issue. Nature Cell Biol 2002;4(suppl 1): s33-40.
Saiyed H, Dewan A, Bhatnagar V, Shemov U, Shenoy R, Rajmohan H, et al. Effect of Endosulfan on male reproductive development. Env Health Perspect 2003;111: 1958-62.
Swan SH, Kruse RL, Liu F, Barr DB, Drobnis EZ, Redmon JB, et al. Semen quality in relation to biomarkers of pesticide exposure. Env Health Perspect 2003;111: 1478-84.
Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen Z, et al. Phthalate exposure and human semen parameters. Epidemiology 2003;14: 269-77.
Cobellis L, Latini G, De Felice C, Razzi S, Paris I, Ruggieri F, et al. High plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis. Hum Reprod 2003;18: 1512-5.
Latini G, De Felice C, Giuseppe P, Del Vecchio A, Paris I, Ruggieiri F, et al. In utero exposure to di-(2-ethylhexyl)-phthalate and human pregnancy duration. Environ Health Perspect 2003;111: 1783-5.
Foster W, Chan S, Platt L, Hughes C. Detection of endocrine disrupting chemicals in samples of second trimester human amniotic fluid. J Clin Endocrinol Metab 2000;85: 2954-7.
Cohn BA, Cirillo PM, Wolff MS, Schwing PJ, Cohen RD, Sholtz RI, et al. DDT and DDE exposure in mothers and time to pregnancy in daughters. Lancet 2003;361: 2205-6.
Storgaard L, Bonde JP, Ernst E, Spano M, Andersen CY, Frydenberg M, et al. Does smoking during pregnancy affect sons' sperm counts? Epidemiology 2003;14: 278-86.(Richard M Sharpe, senior )
Correspondence to: R M Sharpe r.sharpe@hrsu.mrc.ac.uk
Introduction
Though this article is primarily an overview of the current evidence for reproductive effects resulting from exposure to environmental synthetic chemicals, it is relevant to the debate on wider potential health effects of such exposures. The review was compiled after detailed literature searches and cross referencing and scrutiny of relevant websites on environmental chemicals (see educational resources box). After revising the article in light of reviewers' comments, we sought the opinion of an expert toxicologist in industry to ensure balance in the review.
In this hugely contentious area, polarised opinions predominate (because of the lack of definitive data). There are enormous difficulties in establishing whether exposure to individual chemicals or to chemical mixtures causes harm, as adverse effects may not manifest until many years after exposure (for example, in adulthood after fetal exposure). This difficulty must be factored into any discussion of this topic.
Individuals versus populations, hazard versus risk
An endocrine disruptor is a chemical with the potential to alter hormone action within the body.1 The first endocrine disruptors identified were synthetic chemicals that had weak intrinsic hormonal or anti-hormonal activity, usually oestrogenic or anti-androgenic activity.1 Such compounds, when in the body, have the potential to interact with oestrogen or androgen signalling mechanisms (fig 1). Many ubiquitous environmental chemicals, including organochlorine chemicals, and numerous synthetic chemicals prevalent in developed societies (phenolic compounds, for example) are endocrine disruptors.1 w5 As endocrinology textbooks show, disturbance of hormonal homeostasis can result in clinical problems. However, it remains a topic of heated debate as to whether the potential of endocrine disruptors to disrupt hormone action and cause ill health in humans is a reality or merely a remote, theoretical possibility. What has fuelled this debate has been the increase in incidence of two hormone dependent disorders in humans over the past 70 or more years, namely breast cancer8 and testicular dysgenesis syndrome (comprising low sperm counts, testicular cancer, cryptorchidism, and hypospadias) (fig 2).8-10
Fig 1 Potential pathways of endocrine disruption by environmental chemicals. DDE=1,1-dichloro-2, 2-bis(p-chlorophenyl)ethylene; PAHs=polycyclic aromatic hydrocarbons; PCBs=polychlorinated biphenyls; TBT=tributyltin
Fig 2 Trends in reproductive health, United States (for data sources see bmj.com)
Out of this concern, epidemiological studies were prompted, focusing on exposure to organochlorine chemicals and breast cancer, because many organochlorine chemicals are oestrogenic and, also, they are lipophylic and can accumulate in breast fat. One initial study produced evidence linking organochlorine chemical exposure to increased risk of breast cancer,w6 but most subsequent studies have not confirmed this.11 These have included studies in different countries and those that evaluated exposure to organochlorine chemicals many years before breast cancer developed.11 Although these results are reassuring, doubts remain about whether the most important chemicals were measured,12 w2 whether exposure in the correct age window was evaluated,w9 and what effect mixtures of chemicals may have.13 Present evidence suggests that exposure, as an adult, to organochlorine chemicals alone is not a major determinant of breast cancer. Indeed, it seems intuitively unlikely that endocrine disruptors with weak intrinsic oestrogenic activity1 13 can be as important hormonal players in the aetiology of breast cancer as the woman's own potent endogenous oestrogens.14
For testicular dysgenesis syndrome in males, the aetiological involvement of endocrine disruptors is mainly theoretical.10 Testicular dysgenesis syndrome is thought to arise during early pregnancy. Measuring exposure of the human fetus to chemicals and relating this to disorders that may arise decades later (low sperm counts, testis cancer) has major logistical problems. However, a recent study that reported higher levels of organochlorine chemicals in mothers of men with testicular cancer,15 and new discoveries about phthalates (see below), have reawakened interest in the possible aetiological involvement of environmental chemicals in testicular dysgenesis syndrome.w9
"Trojan horse" environmental chemicals
Though most concern about effects of environmental chemicals has focussed on fetal effects (for example, in testicular dysgenesis syndrome),10 17 w5 recent studies point also to postnatal effects. For example, exposure of boys to endosulfan is associated with delayed puberty, though this could have resulted from prenatal exposure.18 More dramatically, fertile men in an agricultural area of Missouri have been shown to have sperm counts about 40% lower than men in three urban US areas,w13 and to have higher urinary concentrations of three currently used pesticides.19 Similarly, direct measurement of certain phthalate metabolites is significantly related to reduced semen quality in men,20 endometriosis in women,21 and shorter gestation periods in pregnant women.22 Although these new findings are suggestive, for none is the mechanism of the chemical's effect self evident. This leaves doubts as to whether the measured chemicals are the real culprits or are surrogates for other chemical exposures or lifestyle practices.
Warnings from wildlife studies?
Human exposure to environmental synthetic chemicals has changed considerably in the past 70 years. This period has witnessed major changes in our diets, lifestyle, and social practices, some of which may be having profound effects on human health. If environmental chemicals are exerting adverse health effects in humans, these are likely to be small in relation to those caused by our dietary and lifestyle changes, although these factors may interact.w21 w22 Moreover, proving that environmental chemicals do—or do not—cause health problems in humans against this changing background is challenging. Nowhere is this truer than in evaluating the impact of maternal exposures in pregnancy that may affect health of the fetus in later life. This is unquestionably the greatest concern,1 and we believe that alternative precautionary strategies must be adopted, which seek to eliminate or minimise unnecessary risks to the fetus, even in the absence of clear proof of harm. Some of these steps can be taken by individuals—for example, lifestyle changes in women seeking to become pregnant (stopping smoking, reduced use of cosmetics and body creams). Reducing exposures by reducing release of chemicals to the environment, however, requires action by industry and government. The proposals by the Royal Commission on Environmental Pollution as to how this may be achieved (box) seem to be a practical and effective path towards such a goal.
References w1-w26 and extended explanations of the figures are on bmj.com
Contributors: The authors are both employed and paid by the Medical Research Council (MRC) and each heads a research team, focused on the causes of abnormal male reproductive development and function, within the MRC Human Reproductive Sciences Unit. RMS has a longstanding interest in the area of endocrine disruptors and is currently chairman of the UK Society for Endocrinology Expert Group on this topic.
Funding: RMS has received research funding from ECETOC (European Consortium on the Ecotoxicology of Chemicals) and AstraZeneca within the past five years.
Competing interests: RMS and DSI have both received reimbursement of travel expenses for attending meetings sponsored by pharmaceutical companies or the chemical industry.
References
Damstra T, Barlow S, Bergman A, Kavlock R, Van Der Kraak G, eds. Global assessment of the state-of-the-science of endocrine disruptors. International Programme on Chemical Safety, 2002. http://ehp.niehs.nih.gov/who/ (accessed 3 Feb 2004).
Czene K, Lichtenstein P, Hemminki K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family-cancer database. Int J Cancer 2002;99: 260-6.
Jeyaratnam J. Acute pesticide poisoning: a major global health problem. World Health Stat Q 1990;43: 139-44.
Second Health and Nutrition Examination Survey (NHANES). Report on human exposure to environmental chemicals. Atlanta: National Center for Environmental Health, 2003. (Publication No 02-0716.) www.cdc.gov/nceh/dls/report/ (accessed 3 Feb 2003).
Mylchreest E, Sar M, Cattley R, Foster PMD. Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. Toxicol Appl Pharmacol 1999;156: 81-95.
Blount BC, Silva MJ, Caudill SP, Needham LL, Pirkle JL, Sampson EJ, et al. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect 2000;108: 979-82.
Koch HM, Drexler H, Angerer J. An estimation of the daily intake of di (2-ethylhexyl) phthalate (DEHP) and other phthalates in the general population. Int J Hyg Environ Health 2003;206: 1-7.
Surveillance, Epidemiology, and End Results (SEER) Program SEER*Stat Database: Incidence—SEER 9 Regs Public-Use, Nov 2002 Sub (1973-2000), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2003, based on the November 2002 submission. http://seer.cancer.gov/ (accessed 3 Feb 2003).
Huyghe E, Matsuda T, Thonneau P. Increasing incidence of testicular cancer worldwide: a review. J Urol 2003;170: 5-11.
Skakkebaek NE, Rajpert-De Meyts E, Main K. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Hum Reprod 2001;16: 972-8.
Calle E, Frumkin H, Henley J, Savitz DA, Thun MJ. Organochlorines and breast cancer risk. CA Cancer J Clin 2002;52: 301-9.
N Evans, ed. Environmental health: what is the connection between chemicals and breast cancer. Breast Cancer Fund and Breast Cancer Action, 2003. www.breastcancerfund.org/environment_evidence_main.htm (accessed 3 Feb 2003).
Rajapakse N, Silva E, Kortenkamp A. Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. Env Health Perspect 2002;110: 919-921.
Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 2002;94: 606-16.
Hardell L, van Bavel B, Lindstrom G, Carlberg M, Dreifaldt AC, Wijkstrom H, et al. Increased concentrations of polychlorinated biphenyls, hexachlorobenzene and chlordanes in mothers to men with testicular cancer. Env Health Perspect 2003;111: 930-4.
Fisher JS, Macpherson S, Marchetti N, Sharpe RM. Human `testicular dysgenesis syndrome': a possible model based on in utero exposure of the rat to dibutyl phthalate. Hum Reprod 2003;7: 1383-94.
Sharpe RM, Franks S. Environment, lifestyle and infertility—an inter-generational issue. Nature Cell Biol 2002;4(suppl 1): s33-40.
Saiyed H, Dewan A, Bhatnagar V, Shemov U, Shenoy R, Rajmohan H, et al. Effect of Endosulfan on male reproductive development. Env Health Perspect 2003;111: 1958-62.
Swan SH, Kruse RL, Liu F, Barr DB, Drobnis EZ, Redmon JB, et al. Semen quality in relation to biomarkers of pesticide exposure. Env Health Perspect 2003;111: 1478-84.
Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen Z, et al. Phthalate exposure and human semen parameters. Epidemiology 2003;14: 269-77.
Cobellis L, Latini G, De Felice C, Razzi S, Paris I, Ruggieri F, et al. High plasma concentrations of di-(2-ethylhexyl)-phthalate in women with endometriosis. Hum Reprod 2003;18: 1512-5.
Latini G, De Felice C, Giuseppe P, Del Vecchio A, Paris I, Ruggieiri F, et al. In utero exposure to di-(2-ethylhexyl)-phthalate and human pregnancy duration. Environ Health Perspect 2003;111: 1783-5.
Foster W, Chan S, Platt L, Hughes C. Detection of endocrine disrupting chemicals in samples of second trimester human amniotic fluid. J Clin Endocrinol Metab 2000;85: 2954-7.
Cohn BA, Cirillo PM, Wolff MS, Schwing PJ, Cohen RD, Sholtz RI, et al. DDT and DDE exposure in mothers and time to pregnancy in daughters. Lancet 2003;361: 2205-6.
Storgaard L, Bonde JP, Ernst E, Spano M, Andersen CY, Frydenberg M, et al. Does smoking during pregnancy affect sons' sperm counts? Epidemiology 2003;14: 278-86.(Richard M Sharpe, senior )