Sex Ratio Changes as Sentinel Health Eventsof Endocrine Disruption NICOLAS A. VAN LAREBEKE, MD, PHD, ANNIE J. SASCO, MD, DRPH,

The production and widespread use of synthetic chem-icals since the 1940s have resulted in ubiquitous con-tamination of fish, wildlife and human populations.
Since the publication of Silent Spring by Rachel Carson,1 humankind has been aware of the wide-spread effects of synthetic chemicals on popula- Since the 1960s, observers have documented major tions of fish and wildlife, and of the potential for effects damage to wildlife reproduction across the globe, and on human health. The exposures to and effects of subsequently, damage to reproductive health in these risks of “modernity” have not only been difficult exposed humans as well. The sex ratio in human com-munities and populations can be readily measured to to perceive without the instruments of science2 but also ascertain whether reproductive effects, such as subtle have been highly contested, particularly by industrial birth defects of the reproductive tract caused by expo- interests and the new social movements for health and sures to chemicals, might be occurring. Male to female environment.3,4 The challenge for both occupational sex ratios appear to be declining in populations in sev- and environmental epidemiologists, as well as the eral parts of the globe, possibly as a result of prenatal public, in undertaking this task has been to find exposures to chemicals. Sex ratio data for communities unequivocal markers of biological effects and to relate with unusual occupational or environmental exposures the effects unambiguously to specific exposures, in can be compiled using traditional epidemiological order to make causal statements on which regulatory techniques in pursuit of environmental justice. Local, regional and national population health researchers Thirty years after the publication of Silent Spring, Dr and occupational hygienists can use health statistics toexamine sex ratios as sentinel health events that might Theo Colborn formulated the hypothesis of endocrine portend patterns of subtle structural birth defects of disruptors.5 It was based on observations of chemically- the reproductive tract and functional deficits in neu- induced reproductive and developmental anomalies in rodevelopment. Key words: reproductive health, sex Great Lakes gulls6 and advances in understanding the ratio, endocrine disruptors, pollution, environment, mechanisms of action of diethylstilbestrol and other xeno-estrogens (synthetic substances with estrogenicactivity).7,4 This provided a unifying explanatory prin- I N T J O C C U P E N V I R O N H E A LT H 2 0 0 8 ; 1 4 : 1 3 8 – 1 4 3
ciple for many of the observations of effects on fish,wildlife and human populations, such as the reproduc-tive and developmental anomalies in alligators,8 and N. van Larebeke acknowledges financial support from the Min- led to an explosion of new experimental, epizootiolog- istry of the Flemish Community (Department of Economics, Science ical and epidemiological research on the effects of and Innovation; Flemish Agency for Care and Health; and Depart- chemicals during the past decade. For example, recent ment of Environment, Nature and Energy). Received from Study studies have documented disturbing reproductive Centre for Carcinogenesis and Primary Prevention of Cancer, GhentUniversity, Belgium (NAvL); Epidemiology for Cancer Prevention, effects of ambient levels of the pesticide atrazine on Victor Segalen Bordeaux 2 University, France (AJS); Occupational frogs, characterised by feminization of males exposed Health Clinics for Ontario Workers, Sarnia, Canada (JTB, MMK); to concentrations that can be encountered through Occupational and Environmental Health Research Group, Univer- permitted uses in the United States.9 In humans, stud- sity of Stirling, Scotland (MG, AW). Address correspondence and ies of the effects of chemicals on reproduction and requests for reprints to: Prof. Nicolas A. van Larebeke, Study Centrefor Carcinogenesis and Primary Prevention of Cancer, Ghent Uni- development have been fraught with uncertainties10 versity , University Hospital 3K3, De Pintelaan 185 , B 9000 Gent, Bel- and in some cases have been heavily contested.11 Con- gium; e-mail: <[email protected]>. cerns have been raised in particular about the effects of Disclosures: N. van Larebeke reports working occasionally as an prenatal exposures in males, including a predisposition advisor to various non-governmental organizations, and to Veolia, to cryptorchidism and hypospadias at birth, increased Inc. (a waste management corporation). The remaining authorsreport no conflicts of interest.
risk of testicular cancer following puberty and declin- ing semen quality.12 In females, concerns include issues based not only on the evidence but also on the threat of premature breast development,13,14 precocious the evidence posed to the continuing profitability of puberty15 and a predisposition to the development of the chemical products in question. The Academy finally concluded that while there were clear indica- The proximity of many urban and rural populations tions of reproductive and developmental disruption in to chemical landfill sites, incinerators and chemical animals, the evidence regarding such effects in humans manufacturing, as well as the common use of chemical was equivocal. The Academy explained that xeno-estro- products in modern life, result in widespread human gens were at least a thousand times less powerful than exposures to a great variety of compounds, some of endogenous hormones, and held that the levels which have endocrine-disrupting activity. The challenge encountered by humans were low and so were unlikely is to detect these otherwise imperceptible exposures to wield any serious effects on human health. through the identification of sentinel health eventsoccurring in the exposed populations, particularly NEW EPIDEMIOLOGICAL STUDIES
those that reliably indicate effects on reproduction,development and population viability in the animal In the past decade, there have been several new epi- kingdom. In the past thirty years, many communities demiological papers (reviewed by Aitken et al.22) that have become aware that they are highly exposed to point towards widespread declines in sperm quality and chemical wastes and releases and have organized to increases in testicular cancer incidence, and show that undertake health surveys through epidemiology stud- these likely have an endocrine etiology.23 Researchers ies.3,4 The measure should be sufficiently simple so that have recently reported declining levels of testosterone it can be readily used, not only by professional epidemi- in U.S. males of 1% per year, the same rate of decline ologists tracking changes in large populations, but also seen for sperm concentrations.24 There has also been by communities as part of their methods for investiga- speculation that testicular dysgenesis syndrome25 origi- tion of the effects of local contamination. nates from conception and can result in a cascade of One such sentinel marker that is proving valuable to defects in Sertoli and Leydig cells that ultimately affect health researchers and the public is the simple expedi- maldescent of the testes, cryptorchidism, fertility and ent of comparing the number of males with the the risk of testicular cancer.26 It seems likely that early number of females born and calculating the sex ratio.
exposures, occurring in a critical time window during This metric has been used extensively to document fetal life, are implicated in this testicular dysgenesis syn- declines in the proportion of males born in many coun- drome and might also contribute to the risk of other tries (reviewed by Davis et al.17), most recently in cancers.27 Others have noted that mothers with higher United States and Japanese populations.17 In addition, levels of phthalates in their blood during pregnancy it has been used in a small Chippewa community sur- have a significantly greater probability of bearing male rounded by chemical manufacturing plants in Sarnia, infants with reduced ano-genital distance, a marker for Ontario, Canada.18 The purpose of this commentary is testicular dysgenesis in rodents.28 Residues of anabolic not only to explore the scientific aspects of this epi- steroids and other xenobiotics used in food production demiological endpoint as a marker of toxicological may pose long-term risks for developmental processes effects within the wider context of the science of in males. For example, in a large study of sperm con- endocrine disruptors, but also to locate this science centration and fertility in American men, there was a within social, economic and political contexts.19, 20 negative association with the number of servings ofbeef their mothers ate per week while pregnant.29 ENDOCRINE DISRUPTORS:
While the negative association is likely attributable to A CONTESTED AREA OF SCIENCE
animals treated with hormonal growth promoters,other interpretations of these findings are possible.30 For more than a decade, the hypothesis of endocrinedisruption has been a contested area of science.21 Some NEW MECHANISTIC STUDIES
scientists have argued that isolated incidents of highlevels of chemical contamination have affected the In addition to these new epidemiological studies, health and reproduction of non-human organisms, but research on mechanisms of action has reduced many of that the levels of contamination have generally been far the uncertainties formerly associated with the too low to have had effects on human beings. In the endocrine disruptor hypothesis.11 Replication of stud- late 1990s, the U.S. National Academy of Sciences11 set ies undertaken at extremely low doses have convinc- up a committee to examine the evidence on endocrine ingly demonstrated the inverted-U-shaped dose- disruptors and the claims that there were irreversible response curves familiar to endocrinologists, with the developmental effects from exposures to low levels of decreases in effects at higher doses. For example, vom contamination with certain chemicals. The committee Saal and Welshons31 have shown that extremely low was characterised by an extreme polarization of views concentrations of xeno-hormones, such as bisphenol VOL 14/NO 2, APR/JUN 2008 • Sex Ratio Changes as Sentinel Health Events
A, cause hormone-like effects that are often not seen at both before and after the onset of disease.56,57 The low higher concentrations, which can however lead to sex ratio before the disease suggest that this hormone other detrimental effects. These low-dose findings have profile is a potential cause of testicular cancer. challenged all of traditional toxicology, which has been As to mechanisms, hormones and xeno-hormones based on high dose testing and linear dose-response might affect sex ratio through the induction of a change relationships as a reflection of the prevailing paradigm in testosterone/human chorionic gonadotropin (HCG) of “dosis facit venenum”: the dose makes the poison.
ratio in men. Alternatively or more generally, they might Another anomalous mechanism that supports the affect sex ratio through a change in imprinting of endocrine disruptor hypothesis concerns receptor gametes or through a change in DNA methylation affect- binding. Receptors bound to xenobiotic ligands do not ing the embryo resulting in differential mortality of male have exactly the same influence on gene expression as versus female embryos. Gametic (genomic) imprinting receptors bound by endogenous ligands.32,33 In review- of some genes is regulated through an imprinting con- ing the state of evidence on bisphenol A, vom Saal and trol region that contains sequences binding nuclear hor- Weshons31 pointed out that blood levels in many mone receptors,58 so it seems possible that sex hormones human populations exceed levels that affect some cell could affect genomic imprinting. Hormones and xeno- functions and cause adverse effects in animals. hormones have been shown to affect DNA methylation Since the contentious report of the U.S. National Academy of Science,11 further mechanistic evidence con-cerning the physiological timing and the critical win- NEW SEX RATIO STUDIES IN HUMANS
dows of development has accumulated, boosting thecredibility of the endocrine disruptor hypothesis. A new Endocrine disruptors, particularly xeno-estrogens, pose paradigm of the “developmental origins of human special problems for males, and there is new epidemio- health and disease” (DOHaD) has been proposed,34,30 logical evidence of effects occurring in specific popula- and is playing an important role in understanding the tions. Recently Canadian researchers McKenzie et al.18 effects of low-dose exposures to endocrine disruptors.
investigated the male-to-female sex ratio in the Aamjiw- Of utmost importance is the realization that intrauterine naang First Nation in Sarnia, Ontario. This Great Lakes programming of physiological systems occurs at the community, which lives amid a large number of petro- gene, cell, tissue, organ, and system levels and causes chemical plants, has experienced a dramatic and permanent structural and functional changes, which can unprecedented decline in sex ratio: almost 40% of the lead to overt disease, particularly with increasing age.35 boys have been lost. The recent study by Davis et al.17 This programming rests in part on DNA modification shows that a decline in sex ratio is not restricted to a lim- and covalent modifications to histones.36 During critical ited community residing in an area with very particular periods of intrauterine development when epigenetic exposures, but that steady reductions in the births of programming determines tissue differentiation, very low male infants have occurred in the U.S. and Japan over doses of endocrine disruptors might lead to permanent the past four decades. According to this analysis, changes in gene expression underlying infertility and declines in the proportion of males born in Japan 1970– increased risk of cancer later in life.37,38,39,30 1999 and to whites in the United States 1970–2002 areequivalent to a shift from male to female births of SEX RATIO AS AN INDICATOR OF
127,000 and 135,000 births, respectively. ENDOCRINE DISRUPTION
The MacKenzie and Davis studies used different methodologies and were undertaken at very different Mammalian sex ratios at birth are partially controlled by scales. Davis et al.17 used national databases to calculate parental hormone levels around the time of concep- the small but statistically significant declines in the pro- tion.40,41 That endocrine disruptors can induce changes portion of boys born, whereas MacKenzie et al.18 used a in sex ratio has been shown through experiments in very small database to demonstrate the statistically-sig- many animal species including mammals.42–49 But nificant large losses of potential male members of the human data also indicate a probably causal link between Aamjiwnaang First Nation. The similarity of the findings endocrine disruption and changes in sex ratio.50,51 Men despite the very different study sizes shows the need to exposed to endocrine disruptors known to cause low undertake calculations of sex ratio at different scales testosterone/gonadotropin ratios have been reported to from the local to the regional, national and interna- sire significant excesses of daughters.52–54 Incidence of tional levels. The findings also indicate that less-conven- testicular cancer has been rising in many countries over tional sources of data may be useful to document a local the past decades, with evidence of a cohort effect, sug- phenomenon. Different kinds of epidemiologists may gesting that an in utero exposure, possibly to endocrine be needed for each scale. At the regional and larger disruptors, might have been involved. Men with testicu- scales, trained epidemiologists are required for access- lar cancer have a low testosterone/gonadotropin ratio,55 ing massive databases and for undertaking calculations.
and sire a significantly higher proportion of daughters But, as the example of the Aamjiwnaang First Nation van Larebeke et al. • INT J OCCUP ENVIRON HEALTH demonstrated, participatory action research under- cury in the 1950s resulting not only in a higher mortal- taken by a collaboration of staff of a local occupational ity of males resulting in a decrease in sex ratio but also health clinic and members of the local native commu- in selective neuro-developmental anomalies in males.67 nity rapidly identified the change in sex ratio as a sen- It has to be acknowledged that factors other than tinel health event. The observation of the anomaly in environmental ones play a role in sex ratio alterations.
sex ratio led to further investigation of health concerns, Increased age of parents,68 parents’ cohabitation initially using qualitative methods, followed by quantita- before conception,69 stress due to war or unfavourable tive surveys of contamination and health effects.
economic conditions,70 greater use of pharmaceuticals, Through such collaborations in population-based epi- in particular drugs used for treatment of childhood demiology, the true extent of the health issues within cancer,71 as well as alcohol and tobacco consumption72 contaminated communities can be established, the also play a role which may differ by country and social underlying causes of disease or condition can be class. Yet, these factors are unlikely to explain marked hypothesized for further investigation, and the commu- changes in otherwise stable communities, such as the nity can empower itself to bring about social change.61 one observed in Sarnia. At a national level in the U.S., Such methods have been used in Canada and in other the global alcohol and tobacco per capita consumption countries62,63 to overcome the limitations of traditional went down at the time the Davis study17 was carried out, scientific approaches in responding to occupational although these findings do not necessarily reflect the hazards and the contamination of communities.64 trend for women and pregnant women in particu- The rapid identification of the sex ratio anomaly lar.73,74 Whereas it is reassuring to note there has been resulted in an immediate, deep rapport between the a decrease in alcohol-related conditions in newborns,75 researchers from the clinic and the members of the smoking rates have increased among pregnant women community. In our societies, such research is necessary from African American and low socioeconomic status but, too frequently at the local level, the boundaries around professions and the loyalties to particular insti- Successful forensic research to identify and locate tutions can undermine respect and lead to distrust the source of exposures to endocrine disruptor chemi- between those affected and those charged with pro- cals requires the involvement of many disciplines and a tecting public health.3,4 For example, a local anomaly willingness of investigators to cross traditional discipli- discovered by civil society researchers can be made to nary boundaries. For example, an observation of a “disappear” by officials measuring the same outcome at change in the sex ratio has immediate psycho-social a larger scale, thereby diluting the local exposed popu- consequences, and, in addition to epidemiologists, lation within a larger unexposed or less-exposed popu- chemists and toxicologists, trained sociologists, anthro- lation, leading to exposure misclassification and reduc- pologists and psychologists are needed as an integral ing the likelihood of detecting the effect.65 part of research teams in “toxic-assaulted communi- The recognition of a sentinel event, such as a change ties.”61 These disciplines are needed to reveal the in sex ratio, poses serious questions about the implica- power relationships within the affected community and tions of the event for futher research or action. Many between the affected community and the larger com- factors in sex ratio changes have been identified, and munity, its health authorities and other institutions. For the etiology of the long-term trends is likely to be multi- it is not only a matter of solving the toxicological rid- causal.17 Further research is needed to identify the con- dles, but also finding the technical and political means tribution of the great variety of known risk factors to the to resolve the situation. For those seeking environmen- changes in sex ratio calculated from national popula- tal justice, the simplicity of the sex ratio metric is a tion statistics. This contrasts with the Aamjiwnaang situ- means of empowering disadvantaged communities in ation, in which the proportion of boys to girls was close their struggles against powerful interests. to the national ratio during the 1980s and early 1990s.18In this cases, there was a well-defined point of inflection CONCLUSIONS
potentially indicating exposure to a specific risk factorthat started around 1995. In contrast to other locations, In both animals and humans, changes in sex ratio are such as Seveso, Italy where a 2,4,5–trichlorophenol associated with certain pathological conditions known explosion in 1976 resulted in an immediate loss of to be at least in part due to endocrine disruption.
males with subsequent recovery,66 there has been a Observations based on animal experiments and human gradual progressive decline in the sex ratio among the epidemiology indicate that the sex ratio of a popula- Aamjiwnaang over more than a decade. Because the tion is a valuable indicator of endocrine disruption.
likely agents are known to be teratogenic, these obser- Most effects of endocrine disruption, such as testicular vations also indicate the need to look for other co-mor- cancer, hypospadias or cryptorchidism, are rare events.
bidities such as neuro-developmental deficits or con- In contrast, the births of boys and girls are routine daily genital abnormalities. For example, the Japanese occurrences. The calculation of the sex ratio is a useful community at Minamata was exposed to methyl mer- parameter in epidemiological studies at scales ranging VOL 14/NO 2, APR/JUN 2008 • Sex Ratio Changes as Sentinel Health Events
from the local to national, and is a useful tool for study- 14. Gulledge CC, Burow ME, McLachlan JA Endocrine disruption ing the effects of long-term, low level, and long-past in sexual differentiation and puberty. What do pseudoher-maphroditic polar bears have to do with the practice of pedi- atrics? Pediatr Clin North Am. 2001;48: 1223-1240. In light of these observations, it is important for pop- 15. Den Hond E, Schoeters G. Endocrine disruptors and human ulation health researchers to conduct both routine sur- 16. Maffini MV, Rubin BS, Sonnenschein C, Soto AM. Endocrine veillance and specific studies using the following three disruptors and reproductive health: the case of bisphenol-A.
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VOL 14/NO 2, APR/JUN 2008 • Sex Ratio Changes as Sentinel Health Events


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