Are EDCs Blurring Issues of Gender? Although scientists have postulated a wide range of adverse human
health effects of exposure to endocrine-disrupting chemicals (EDCs),
the nexus of the debate is the concern that prenatal and childhood
exposure to EDCs may be responsible for a variety of abnormalities
in human sexuality, gender development and behaviors, reproductive
capabilities, and sex ratios. Scientists today are asking hard questions
about potential human effects: Do EDC exposures impair fertility
in men or women? Can they cause sexual organ malformations, stunted
reproductive development, or testicular or breast cancer? Do fetal
exposures to EDCs alter sex phenotypes? Do they change later gender-related
neurobiological characteristics and behaviors such as play activity
and spatial ability? Could such exposures even be involved in the
etiology of children born with ambiguous gender?
EDCs include a spectrum of substances that can be loosely classified
according to their known or suspected activity in relation to sex
hormone receptors and pathways. The most-studied and best known are
the environmental estrogens, which mimic estradiol and bind to estrogen
receptors (ERs). ER agonists include the pesticide methoxychlor,
certain polychlorinated biphenyls (PCBs), bisphenol A (BPA; a high
production volume chemical used to make polycarbonate plastic), pharmaceutical
estrogens such as diethylstilbestrol (DES) and ethinyl estradiol,
and phytoestrogens, which occur naturally in many plants, most notably
in soybeans in the form of genistein and related substances. There
are a few known ER antagonists, or antiestrogens. Antiandrogens,
or androgen receptor (AR) antagonists, include the fungicide vinclozolin,
the DDT metabolite p,p´-DDE, certain phthalates (a group
of chemicals used to soften polyvinyl chloride plastics), and certain
other PCBs. And there are other types of EDCs that affect particular
endocrine targets. The various EDCs differ greatly in their potencies
relative to natural hormones, and in their affinity for target receptors.
Some have been shown to act via non-receptor-mediated mechanisms,
for example by interfering with hormone synthesis.
In many well-documented cases of high-level fetal exposures to
known EDCs such as DES, certain PCBs, and DDT, the answer to the
question of whether exposure is associated with gender-related effects
is clearly yes. But high-level exposures such as these are relatively
rare and isolated. The debate today centers on low-dose exposures--generally
defined as doses that approximate environmentally relevant levels--and
the idea that low-dose intrauterine exposure to some EDCs during
certain critical windows of development can have profound, permanent
impacts on subsequent fetal development and adult outcomes.
Critics of this idea maintain that thus far there is no credible
evidence to suggest that low-dose exposures cause any adverse human
health effects. But if low-dose exposures were confirmed to be the
threat that proponents of the concept insist they are, public health
would clearly be at risk, regulatory agencies’ risk assessment
approach would need to be revised, and certain common chemicals--including
some that are massively produced and economically important--would
likely disappear from the marketplace.
In a June 2000 EHP review article on human health problems
associated with EDCs, Stephen Safe, director of the Center for Environmental
and Genetic Medicine at Texas A&M University, concluded that “the
role of endocrine disruptors in human disease has not been fully
resolved; however, at present the evidence is not compelling.” Frederick
vom Saal, a developmental biologist at the University of Missouri-Columbia,
disagrees, particularly in light of the research that’s been
presented in the years since that review. “The jury is not out
on human effects,” he says. “In terms of the amount of information
we have in animals and the amount of information we have in humans, clearly
there is a huge difference, but that’s a lot different than saying the
jury is out on whether EDCs influence humans.” One thing both scientists
might agree on, though, is that right now there are still more questions than
answers.
A Delicate Process
The endocrine system, comprising the hypothalamus, pituitary, testes,
ovaries, thyroid, adrenals, and pancreas, is one of the body’s
key communications networks. It regulates the function of specific
tissues and organs by secreting hormones that act as precise chemical
messengers. Development and regulation of the reproductive system
is one of the major functions of the endocrine system.
Sex determination and development begin early in gestation, with
the differentiation of the embryonic gonad into either testes or
ovaries. If the Sry gene is present on the Y chromosome, it
will, when activated, trigger a complex cascade of hormonal events
that ultimately results in the birth of a baby boy with all of the
requisite male equipment in place and functioning properly. In the
absence of the Sry gene, the end product of the process
will be a baby girl. The female phenotype is considered to be the “default” pathway
for mammalian reproductive development.
|
A question of Y. A Swedish study
of fishermen exposed to CB-153 and p,p´-DDE associated
elevated levels of these chemicals with a higher proportion
of Y-chromosome sperm, suggesting that exposure to EDCs could
skew the ratio of boys to girls.
image: Getty Images |
Differentiation and development of the sexual organs continues
throughout gestation under the guidance of the various sex hormones
(such as estrogen and testosterone) produced by the endocrine system.
For males and females alike, the entire process of reproductive development
is exquisitely sensitive to minute changes in levels of the sex hormones,
particularly during certain critical windows of development.
In papers published in the Journal of Animal Science throughout
1989, vom Saal demonstrated this sensitivity in a series of mouse
experiments. These studies showed that in multiple-birth species
it was possible for adjacently positioned male and female fetuses
to transmit tiny amounts of hormones to each other, with pronounced
phenotypic consequences. “We found that a difference of about
a part per billion of testosterone and about twenty parts per trillion
of estradiol [endogenous estrogen] actually predict entirely different
brain structures, behavioral traits, enzyme levels, and receptor
levels in tissues, hormonal levels in the blood--there is nothing
you look for that . . . doesn’t differ in these animals,” says
vom Saal.
Such a delicately timed and precisely controlled process presents
a myriad of opportunities for perturbation from exposure to EDCs.
These chemicals mimic hormones, and can disrupt differentiation and
development in a wide variety of ways, by duplicating, exaggerating,
blocking, or altering hormonal responses. The developing fetus and
early neonate may lack the protective metabolic mechanisms present
in adults that help detoxify and break down chemicals, maintaining
homeostasis in the system. Also, tissues are rapidly dividing and
differentiating in the fetus, and such a high level of cell activity
is vulnerable to disruption of normal development. With such small
body mass in the fetus and child compared to an adult, exposure levels
may be amplified in terms of relative dosages reaching target tissues.
And sometimes, exogenous EDCs may show very low binding to plasma
hormone-binding proteins and thus roam the body in an unbound state,
with unknown effects.
Much of what remains to be discovered about the impacts of EDC
exposures on the fetus relates to a new concept called the developmental
origins of health and disease (until recently known more commonly
as the fetal basis of adult disease). “People are just now
recognizing that this is indeed a possibility,” says NIEHS
scientist Retha Newbold, a pioneer in the study of endocrine disruption
who has spent decades researching the effects of exogenous estrogens,
particularly DES. “Developmental exposure to low doses of EDCs
may not lead to malformation or to anything you can look at and immediately
recognize as a problem,” she says. “But it still could
have long-term effects, such as alterations in metabolism, alterations
causing cancer later on, or alterations causing infertility.”
Evidence of Effects
Reproductive and developmental abnormalities linked to EDC exposures
have now been documented in birds, frogs, seals, polar bears, marine
mollusks, and dozens of other wildlife species. For example, alligators
in Lake Apopka--one of Florida’s most polluted lakes due to
extensive farming activities around the lake, the presence of a sewage
treatment facility, and a major 1980 spill of pesticides including
DDT and DDE--have been shown to have been “feminized.” That
is, zoologist Louis J. Guillette, Jr., and colleagues first reported
in the August 1994 EHP, the males have shortened penises and
low levels of testosterone, while the females have excessive levels
of estrogens. Sex reversal (in which an animal of one sex matures
with the reproductive organs and capabilities of the other sex) and
skewed sex ratios (in which there is an unusually greater proportion
of one sex than the other) have been seen in several fish populations,
particularly colonies living in close proximity to pulp and paper
mills and sewage treatment plants. Other reports have shown reproductive
effects among wildlife resulting from exposure to EDCs excreted into
the water supply by women taking birth control pills.
Many of the adverse outcomes seen in wildlife populations have
been replicated in laboratory experiments, confirming the role of
EDCs in their occurrence. Among the papers reporting such confirmation
were a May 1997 article in EHP, in which Guillette, D. Andrew
Crain, and colleagues replicated alterations in steroidogenesis (the
production of sex hormones) in alligators. More recently, in the
December 2004 issue of EHP, Jon Nash and colleagues showed
that long-term laboratory exposure to environmental concentrations
of the pharmaceutical ethinyl estradiol caused reproductive failure
in zebrafish.
According to a report on EDCs published in volume 75, issue 11/12
(2003) of Pure and Applied Chemistry by the Scientific Committee
on Problems of the Environment/International Union of Pure and Applied
Chemistry (SCOPE/IUPAC), more than 200 animal species are either
known or suspected to have been affected by these chemicals. “The
weight of evidence for endocrine disruption in wildlife is really
overwhelming,” says Joanna Burger, a professor of cell biology
and neuroscience at Rutgers University who cochaired the SCOPE/IUPAC
project.
|
Watching wildlife. Research has documented
reproductive and developmental abnormalities linked to EDC
exposures in wildlife species such as alligators and polar
bears, although what these results mean for humans is still
unknown.
images, left to right: Digital Vision; Guarawa Kumar/iStockphoto |
The SCOPE/IUPAC report was less definitive on the extent of human
effects of endocrine disruptors. “It is too early to reach
firm conclusions about whether human populations are seriously at
risk from potential exposures to [EDCs], and further vigilance is
clearly required,” the authors wrote. “However, it is
somewhat reassuring that after substantial research in the past decade,
there have been no conclusive findings of low-level environmental
exposures to [EDCs] causing human disease.”
The report further notes, however, that “[c]hemical interferences
with steroid biosynthesis and metabolism can produce adverse health
effects, even though the inducing agent would not be detected as
an [EDC] using receptor-based test systems. This is an important
area of study because some examples of [endocrine disruption] occurring
in animals derive from exposure to inhibitors of steroidogenic enzymes
such as 5a-reductase and aromatase.
Some such agents are known to be active in humans and are used successfully
in the treatment of a range of human hormonal conditions.” The
authors suggested that evaluation of such effects will require integrated
screening that incorporates in vitro and in vivo technologies.
A comprehensive report issued in 2002 by the World Health Organization’s
International Programme on Chemical Safety, titled Global Assessment
of the State-of-the-Science of Endocrine Disruptors, reached
similar conclusions. The report stated that “although it is
clear that certain environmental chemicals can interfere with normal
hormonal processes, there is weak evidence that human health has
been adversely affected by exposure to endocrine-active chemicals.
However, there is sufficient evidence to conclude that adverse endocrine-mediated
effects have occurred in some wildlife species.” Citing the
fact that studies to date examining EDC-induced effects in humans
have yielded inconsistent and inconclusive results, the group wrote
that, although that explains their characterization of the evidence
as weak, “[that] classification is not meant to downplay the
potential effects of EDCs; rather, it highlights the need for more
rigorous studies.”
The Global Assessment further states that the only
evidence showing that humans are susceptible to EDCs is currently
provided by studies of high exposure levels. There is, in fact, clear
evidence that intrauterine EDC exposures can alter human reproductive
tract development and physiology. The most thoroughly characterized
example is DES, the synthetic estrogen prescribed to millions of
pregnant women in the United States and elsewhere from the 1940s
to the 1970s to prevent miscarriage. The drug is known to have caused
a rare form of vaginal cancer in thousands of daughters of women
who took DES, as well as a variety of adverse reproductive tract
effects in both the daughters and sons of those women.
The DES situation could be seen as a worst-case scenario for prenatal
EDC exposure--the deliberate delivery of a potent estrogenic chemical
in high doses. Viewed another way, it has provided researchers a
rare opportunity to study the effects of prenatal EDC exposure in
a relatively controlled fashion, with a well-defined population and
well-characterized exposure to a single potent agent.
Over the course of her research, Newbold has developed a mouse
model of DES exposure that has proven extremely useful in studying
the effects of DES and other environmental estrogens, particularly
those outcomes that may be manifested only later in life. “With
the experimental model, there are a lot of questions we can ask with
DES that will tell us about the weaker environmental estrogens,” she
says. “We can change the timing of exposure and the amount
of exposure, and we can look at different target tissues.”
The animal model has replicated numerous abnormalities reported
in DES-exposed humans, and has also predicted some human outcomes. “We
have published documentation [see, for example, the October 1985
issue of Cancer Research and volume 5, issue 6 (1985) of Teratogenesis,
Carcinogenesis, and Mutagenesis] that a number of the reproductive
anomalies seen in DES-exposed mice, such as retained testes and abnormalities
in the oviduct in females, were also later reported in DES-exposed
humans,” says Newbold.
The Phthalate Connection
But reliable correlations between animal data and human outcomes
have proven elusive, particularly when it comes to showing an association
between human exposures to environmental EDCs at ambient levels (that
is, unrelated to spills or other acute contamination events) and
adverse health effects. That may be about to change for one class
of chemicals--phthalates.
Phthalates are commonly used in a wide variety of consumer products
such as solvents, soft plastics, and cosmetics. The National Health
and Nutrition Examination Survey showed that the majority of the
U.S. population carries a measurable body burden of several phthalates.
There is an extensive body of literature regarding the effects of
prenatal phthalate exposure in rodents. Those effects include an
association between intrauterine exposure and abnormalities in male
animals in a biomarker known as anogenital distance (AGD), or the
distance between the rectum and the base of the penis. AGD has been
shown to be a sensitive measure of prenatal antiandrogen exposure.
This pattern of genital dysmorphology has come to be known as the “phthalate
syndrome.”
In the first study to look at the link between AGD and EDC exposure
in humans, Shanna Swan, a professor of obstetrics and gynecology
at the University of Rochester, and her colleagues collected data
from 85 mother-son pairs participating in the Study for Future Families,
a multicenter pregnancy cohort study. The mothers’ urine was
analyzed for the presence of several phthalate metabolites, and the
infant boys, aged 2-36 months, were examined for genital developmental
characteristics, including AGD, which was standardized for weight
to develop an anogenital index (AGI).
|
Ubiquitous exposure, unknown consequences. Humans are exposed to EDCs through many routes including pharmaceuticals,
air pollution, pesticides, and drinking water, but the effects
of environmental exposure are largely unknown.
all images: Getty Images |
Although the researchers found no sign of frank genital malformations
or disease, they did discover an association between elevated concentrations
of four phthalate metabolites in the mothers and shorter-than-expected
AGI in the infants, as reported in the August 2005 issue of EHP.
And, importantly, shortened AGI was found in infants exposed prenatally
to phthalate metabolites at concentrations comparable to those found
in one-quarter of the U.S. female population. The boys with short
AGI were also significantly more likely to have incomplete testicular
descent (cryptorchidism). “We know that incomplete testicular
descent is a risk factor for poorer semen quality, lower sperm counts,
[impaired fertility], and testicular cancer,” says Swan. Although
it is obviously impossible to predict adult outcomes, she says these
infants may be at risk of testicular dysgenesis syndrome (TDS) in
the future.
TDS is a concept put forth by Danish researcher Niels Skakkebæk
and colleagues, in which four adverse male reproductive end points--impaired
semen quality, cryptorchidism, hypospadias (abnormal location of
the urethra), and testicular cancer--are risk factors for each other.
Says Swan, “The idea is that the development of the testis
is interrupted in fetal life, and that this has consequences in adult
life, as well as at birth. That certainly is something we’ve
seen in rodents, and this study is the first evidence we’ve
seen of TDS in humans.”
Swan’s study is among the first to combine a population-based,
measurable, low-level EDC exposure, observed physiologic effects,
and solid biological underpinnings. Even skeptic Safe says that this
is the kind of study needed to begin to answer the many questions
about EDCs and human health. “This looks to be a good approach,
and suggests a correlation,” he says. “Whether it’s
causal of anything and whether it holds up or not, I don’t
know. It needs to be repeated in different locations and with more
and more integrated measurements.” Swan plans to do just that,
as well as to follow up on her current pregnancy cohort by measuring
gender role behaviors in both the male and female children, who are
now between 2 and 5 years old.
The Phthalate Esters Panel of the American Chemistry Council, a
trade organization based in Arlington, Virginia, maintains that “there
is no well-established and credible evidence for adverse effects
[due to phthalates] in humans at environmentally relevant doses,” says
panel manager Marian Stanley. With regard to Swan’s study,
Stanley says, “It correlated some effects in infant males with
some lower-molecular-weight phthalates, particularly diethyl phthalate,
for which effects in rodents occur only at very high doses, and which
is not considered to pose reproductive or developmental concerns
by reviewing government agencies.”
Stanley also points to questions about the biomarker used in the
study. “The measurement that was used is something that I think
is still subject to debate. You see the AG distance in rodents, and
while it is a marker of something, it is certainly not a biological
effect,” she says. “I think the study has been overinterpreted
by lots of other people [besides] the authors of the study.”
EDCs and Sex Ratios
Sex ratio--the proportion of male to female live births--is very
constant on a worldwide basis, typically ranging from 102 to 108
male births for every 100 female births. In recent years, however,
a number of reports have suggested that environmental and occupational
exposures to EDCs may be altering the sex ratio within given human
populations.
In one such study, appearing in the July 2005 edition of Human
Reproduction, a group of Swedish researchers analyzed blood
and semen samples from 149 fishermen to investigate whether exposure
to the persistent organochlorine pollutants CB-153 (a PCB) and p,p´-DDE
affected the proportion of Y- and X-chromosome-bearing sperm. They
discovered that elevated exposure levels of both chemicals were
positively associated with a higher proportion of Y-chromosome
sperm. The researchers conclude that their findings add to evidence
that exposure to persistent organic pollutants may alter the offspring
sex ratio, with the higher proportion of Y-chromosome sperm likely
tending to lead to a higher proportion of male births.
A study appearing in the October 2005 issue of EHP takes
an epidemiologic approach to the issue. Constanze Mackenzie, a member
of the Faculty of Medicine at the University of Ottawa, and colleagues
report a distinct skewing of the sex ratio within members of the
Aamjiwnaang First Nation community near Sarnia, Ontario. They found
a severe decline in the proportion of boys born among the Aamjiwnaang
over the last five years, and a lesser though still significant decline
over the past ten years. Although no causal factors were determined,
the authors note that the community is located in immediate proximity
to several large petrochemical, polymer, and chemical plants, and
that previous studies--such as those following the 1976 industrial
accident in Seveso, Italy--have shown that exposure to contaminants
such as EDCs can impact sex ratios within small communities near
such industrial facilities. The authors suggest that further assessment
should be pursued to identify potential exposures among community
members. [For more details on this study, see “Shift
in Sex Ratio,” p. A686 this issue.]
How Low Do They Go?
When is a hypothesis no longer a hypothesis, but a validated scientific
concept ready to drive regulatory and policy decision making? When
it comes to the so-called “low-dose hypothesis” regarding
the biological activity or adverse effects of low-dose exposures
to EDCs, that is the key question. The issue has been debated for
years, since vom Saal’s group first published in the January
1997 issue of EHP their findings of enlarged prostate in male
mice whose mothers had been fed low doses of BPA. Today, the controversy
over whether vom Saal’s findings have been sufficiently replicated,
and whether the U.S. Environmental Protection Agency (EPA) should
revise its risk assessment process to reflect the potential for adverse
effects of low-dose EDCs, is still going strong.
Some proponents of the low-dose hypothesis argue that the traditional
toxicologic approach to risk assessment is an inappropriate method
to assess EDCs. The current protocol assumes a linear dose-dependent
response to chemical exposures, determines the lowest level at which
there is an observed adverse effect, and then adds a safety factor
to arrive at an official reference dose--the daily human intake assumed
to be safe. Experimental work by vom Saal and others has postulated
that EDCs exhibit a U-shaped dose-response curve, with biological
activity stimulated at very low doses--often several orders of magnitude
below current reference doses--as well as very high doses.
Proponents also state that the process of endocrine disruption
itself is inherently different from many other toxicologic processes,
affecting a variety of highly sensitive pathways (especially in the
fetus) via novel mechanisms of action, many of which are as yet poorly
understood. Also, they say, endocrine-signaling pathways that mediate
responses to EDCs have evolved to act as powerful amplifiers, resulting
in large changes in cell function occurring in response to extremely
small concentrations.
One chemical that has become a lightning rod in the debate is BPA.
By vom Saal’s count, there are now more than 100 published
peer-reviewed studies showing significant biological effects of low
doses of BPA (almost half published within the last two years) compared
to 21 reporting no effect. He is convinced that widespread exposure
to BPA poses a threat to human health.
Not so, claims Steve Hentges, executive director of the Polycarbonate
Business Unit of the American Plastics Council: “For our purposes,
what we have to know is, does BPA cause health effects in humans
at any relevant dose, particularly at the levels at which people
are actually exposed? When you look at all of the evidence together,
and in particular look at the comprehensive studies that are designed
to look for health effects, you don’t find them.”
The industry group also believes that the weight of evidence does
not support the concept of a low-dose effect for BPA. “And
it’s not just us saying that,” says Hentges. “Indeed,
every government body worldwide that’s looked at it has reached
effectively the same conclusion in terms of how they regulate BPA
or consider regulating it.” He acknowledges that there has
been quite a bit of new research activity in this area within the
past few years, but states that “even though new research has
been conducted, we believe that the weight of evidence has not shifted.”
Where does the EPA stand on these issues? The agency’s Office
of Research and Development is in the midst of implementing a multiyear
plan to set the EPA’s agenda and goals in the area of EDC research.
The plan is part of the agency’s Endocrine Disruptors Research
Program, a five- to ten-year research agenda it started in 2001 to
look comprehensively at the science surrounding EDC exposures and
effects. The integrated program was launched at about the same time
that a congressional mandate, under the 1996 Food Quality Protection
Act, directed the EPA to develop a screening and testing program
for EDCs.
The EPA’s stance is that the jury is still out on both the
public health impacts of EDCs and the need to incorporate low-dose
methodologies into the agency’s risk assessment protocols.
Elaine Francis, director of the Endocrine Disruptors Research Program,
says the EPA needs to conduct a lot more research before any definitive
public health statements can be made about this class of compounds. “When
you look at such a diverse group of organisms that have been impacted
in wildlife, and certainly laboratory rodent species,” she
says, “there is enough concern that we recognize the importance
of developing a body of work in humans to try to characterize any
impact [EDCs] might be having on humans.”
The agency is currently funding three research grants in the area
of low-dose EDC exposures, partly in response to the conclusions
reached in a 2000 peer review and subsequent report on the low-dose
issue held by the National Toxicology Program at the EPA’s
request. In the 2001 Report of the Endocrine Disruptors Low-Dose
Peer Review, that expert panel acknowledged that low-dose effects
had been sufficiently documented at that point in time for the EPA
to consider revisiting its current testing paradigm.
“The general consensus was that more work needed to be done
in this area,” says Francis. “Since that time, we would
still agree that there has not been enough information to indicate
that the existing approaches are ones that would not be valid for
endocrine disruptors. But we left the door open that we would need
to do more research, and the best we could do at this point is to
support and promote research in that area, and we’ve done that.”
Vom Saal is of a different opinion: “In the risk assessment
process for chemicals as currently conducted, the maximum tolerated
dose is used as a reference, and a span of typically not more than
fiftyfold in the dose range is the maximum that anyone ever uses
in the studies. Studies [from the 1 January 2005 issue of Cancer
Research and the April 2005 EHP show] literally millions
of fold below that dose range in adverse effects . . . from BPA,
and when you have that type of unbelievable discrepancy, for the
EPA to come out as it recently did and state that it has no intention
of testing low doses as part of the testing process [implies] that
you no longer have a scientifically based process--it is an entirely
politically driven process, because they are explicitly ignoring
the scientific findings that are out there.”
From her perspective, Newbold feels that although there is no question
that EDCs have low-dose effects, more research needs to be done to
document adverse effects in humans. “We spend an awful lot
of time arguing whether there are low-dose effects or not. That just
infuriates me,” she says. “There are low-dose
effects. There have always been low-dose effects. The
question is, are they adverse? We don’t know, and we’ve
got to design studies to get answers to that question.” She
adds, “In order to take this argument to a whole other level,
we’re going to have to have more epidemiology studies. I know
it happens with mice, but I don’t know what happens with humans.”
Connecting the Gender Dots
It’s premature to call it a theory; at this point, it barely
qualifies as a hypothesis: some observers are putting forth the proposition
that prenatal EDC exposures may affect gender identity--how a person
identifies him- or herself, regardless of physical characteristics.
This idea presupposes two basic concepts: first, that transgenderism
(in which a person experiences “gender dysphoria,” a
strong feeling of having been born the wrong sex) is physiological
in origin, most likely due to events during prenatal neurological
development; second, that intrauterine EDC exposures can and do disrupt
prenatal neurological development.
Reprinted from:
Zhou J-N, Hofman MA, Gooren LJG, Swaab DF. 1995. A sex
difference in the human brain and its relation to transsexuality.
Nature 378:68-70.
|
Gender basis. In a study of the
brain region known as the BSTc, which varies in size by sex,
the volume of the BSTc for male-to-female transsexuals was
analogous to that seen in women, leading the authors to speculate
that the findings “support the hypothesis that gender identity
develops as a result of an interaction between the developing
brain and sex hormones.” |
A paper in the 2 November 1995 issue of Nature, among other
reports, lends credence to the first concept. Jiang-Ning Zhou and
colleagues at the Netherlands Institute for Brain Research studied
heterosexual men and women, homosexual men, and male-to-female transsexuals.
They reported finding a distinctly female brain structure in genetically
male transsexuals (men who had gone through hormonal treatment and
irreversible sexual reassignment surgery to become women). The volume
of the central subdivision of the bed nucleus of the stria terminalis
(BSTc), a sexually dimorphic brain area that is essential for sexual
behavior, is larger in men than in women. Anatomical study results
showed that BSTc volume did not differ significantly between heterosexual
and homosexual men, and that BSTc volume was 44% larger in heterosexual
men than heterosexual women. In the male-to-female transsexuals,
BSTc volume was only 52% that of the reference males--a volume analogous
to that seen in the women. The authors write that these findings “support
the hypothesis that gender identity develops as a result of an interaction
between the developing brain and sex hormones.”
But a study by Wilson C.J. Chung and colleagues published in the
1 February 2002 Journal of Neuroscience complicates this
picture. This group, also from the Netherlands Institute for Brain
Research, reported that BSTc size differentiation between men and
women became significant only in adulthood, implying that the phenomenon
may be more effect than cause. The authors do point out, however,
that the lack of marked sexual differentiation of the BSTc volume
before birth and in childhood does not rule out early gonadal steroid
effects on BSTc functions. They point to earlier animal experiments
showing that fetal or neonatal testosterone levels in humans may
first affect synaptic density, neuronal activity, or neurochemical
content during early BSTc development, and that “[c]hanges
in these parameters could affect the development of gender identity
but not immediately result in overt changes in the volume or neuronal
number of the BSTc.”
On the other side of the ledger, in the June 2002 edition of EHP
Supplements, Bernard Weiss, a professor of environmental medicine
and pediatrics at the University of Rochester, reviewed the existing
literature on sexually dimorphic nonreproductive behaviors as indicators
of endocrine disruption. Weiss made a strong evidence-based case
that “gender-specific regional differentiation of the brain
and, ultimately, its expression in behavior are guided by the gonadal
hormones,” and that the process is subject to interference
by drugs and environmental contaminants. He points out that sex
differences in performance and behavior are not--but should be--a
recognized criterion in developmental neurotoxicity testing.
So who out there is connecting these dots?
Scott Kerlin is a Ph.D. social scientist at the University of British
Columbia. He devotes considerable time to monitoring the international
scientific literature on DES and other EDCs as well as to researching
and writing about the long-term health effects of prenatal DES exposure
on males. He is himself the son of a woman given DES in pregnancy.
Kerlin recently conducted a survey study of 500 members of the
DES Sons International Network, an online resource for men who know
or strongly suspect they were exposed to DES in utero. In
a paper presented in August 2005 at the International Behavioral
Development Symposium in Minot, North Dakota, he reports that more
than 150 respondents identified themselves as having any of a variety
of gender-related disorders. Kerlin does not claim that DES causes
these gender disorders, but feels that his results indicate that
such outcomes should be included in research related to the potential
effects of prenatal EDC exposures.
The Road Ahead
It’s going to be very difficult to ever conclusively answer
the basic question of whether low-level EDC exposures during development
are causing deleterious reproductive or gender-related outcomes in
humans. Scientists agree that one of the major challenges is to address
the issue of mixtures. Typically, researchers look at the impact
of one chemical at a time, but environmental exposures regularly
involve an unpredictable mix of chemicals, with exposures varying
widely in dose and duration. It is unlikely there will ever be a
comprehensive understanding of how the many EDCs in mixtures interact
with each other and with human physiology.
Convincing epidemiologic evidence of adverse effects in humans
is also difficult to come by, but will be necessary to translate
scientific findings into concrete actions to protect public health.
Swan’s study, one of the first of its kind to appear thus far,
may serve as a methodological model for future investigations of
low-level EDC exposures.
Do we know enough now that steps should be taken in the policy
and regulatory realm? Some observers, taking a precautionary approach,
think that we do. For example, there are bills under consideration
in the California and New York legislatures to restrict the use of
certain phthalates in toys, child care products, and cosmetics, and
a California bill would ban the use of BPA in products meant for
use by children aged 3 years or younger. Also, the European Parliament
voted in 2005 to ban the use of three phthalate plasticizers (DEHP,
di-n-butyl phthalate, and benzyl butyl phthalate) in toys
and child care items, and to prohibit the use of three others (diisononyl
phthalate, diisodecyl phthalate, and di-n-octyl phthalate)
in toys and child care items that children can put in their mouths.
Theo Colborn, a professor of zoology at the University of Florida
and author of the 1996 book Our Stolen Future, believes the
time for action is now. “In the animals, it was at the population
level that we really began to realize what was going on,” she
says. “If we’re going to wait to see population effects
for all of these concerns that we have in the human population, it’s
going to be too late.” She points out that we’re already
into the fourth generation of individuals who have been exposed in
utero to chemicals that had never been used before the mid-1930s
or early 1940s.
Swan agrees that there is sufficient knowledge at this point to
call EDC exposures a serious threat to public health. “I don’t
think it’s necessarily a threat to individuals,” she
says, “but I think that as a population we are threatened.
I’m not predicting the end of the species or anything like
that, but I think the increasingly alarming trends that we’re
seeing, in terms of couples that can’t conceive or couples
whose babies have undescended testicles, and so on, can have an impact
on the population as a whole.”
Other observers are not so sure. Harry Fisch, director of the Male
Reproductive Center at Columbia University Medical Center, specializes
in the diagnosis and treatment of male infertility. From his clinical
perspective, other factors--including other exposures--are more important
than EDCs. “The sky is not falling,” he says. “A
lot of times there’s extrapolation from high-dose exposure
to low-dose exposure. I think one of the biggest culprits for the
abnormalities we see that’s been totally ignored is [increased]
parental age. Also, we need to look at things we’re doing to
ourselves before we start blaming low-level chemicals. For example,
what does cigarette smoking do compared to Saran Wrap? What about
the diets we eat, the high-fat intakes? Before we start blaming others,
we need to look at ourselves to determine the impact of our lifestyles.”
Although plastic wrap may not be responsible for human infertility,
the scientific evidence fueling growing concerns about the effects
of ambient environmental exposures to EDCs cannot simply be dismissed. “Vigilance
is the key word here, because there are so many chemicals out there,” says
Burger. “Understanding the effects of chemicals is a three-pronged
approach. It’s being sure that we have wildlife models and
people who are watching wildlife populations to see quickly if something
detrimental happens. It’s having really good epidemiological
studies and vigilance of people in various places. And it’s
backing those two up with laboratory science immediately when a problem
turns up, to try to ascertain the cause quickly.”
Ernie Hood
|