Sex Ratio Changes as Sentinel Health Eventsof Endocrine Disruption
NICOLAS A. VAN LAREBEKE, MD, PHD, ANNIE J. SASCO, MD, DRPH,
JAMES T. BROPHY, PHD, MARGARET M. KEITH, PHD, MICHAEL GILBERTSON, MSC, PHD,
ANDREW WATTERSON, PHD, CSHP
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
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
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
: 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
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 • www.ijoeh.com
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
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.
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.
www.ijoeh.com • 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
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 • www.ijoeh.com
Sex Ratio Changes as Sentinel Health Events
from the local to national, and is a useful tool for study-
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defects of reproductive tract should be routinely carried
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