[Pharmwaste] Are EDCs Blurring Issues of Gender?

[Tenace, Laurie]

http://ehp.niehs.nih.gov/members/2005/113-10/focus.html


Are EDCs Blurring Issues of Gender?=20
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?=20
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=B4-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.=20

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.=20

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.=20

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.=20

A Delicate Process=20
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.=20

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.=20

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.=20

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.=20

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.=20

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."=20

Evidence of Effects=20
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.=20

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.=20


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."=20

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.=20

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."=20

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.=20

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.=20

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."=20

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.=20

The Phthalate Connection=20
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.=20

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."=20

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).=20

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 Skakkeb=E6k 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."=20

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."=20

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."=20

EDCs and Sex Ratios=20
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.=20

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=B4-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.=20

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.]=20

How Low Do They Go?=20
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.=20

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.=20

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.=20

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.=20

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."=20

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."=20

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.=20

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."=20

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.=20

"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."=20

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."=20

>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."=20

Connecting the Gender Dots=20
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.
=20
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."=20

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."=20

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."=20

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.=20

So who out there is connecting these dots?=20

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.=20

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.=20

The Road Ahead=20
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.=20

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.=20

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.=20

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."=20

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."=20

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."

Laurie J. Tenace
Environmental Specialist
Florida Department of Environmental Protection
2600 Blair Stone Road, MS 4555
Tallahassee, Florida 32399-2400
PH: (850) 245-8759
FAX: (850) 245-8811
Laurie.Tenace@dep.state.fl.us
=20
view our mercury web pages at:=20
http://www.dep.state.fl.us/waste/categories/mercury/default.htm
=20
=20