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EMBO reports 5, 1, 16–18 (2004)
doi:10.1038/sj.embor.7400063
A cause without a disease
Endocrine-disrupting chemicals have become a topic of public
concern because they could potentially cause cancer and male infertility. But
evidence for a human health problem is hard to find
Holger Breithaupt
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Endocrine disruptors—or 'gender benders' as they are often
referred to by the public—have become the focus of environmentalists and
public health advocates who decry a slow poisoning of humans and the
environment by the chemical and consumer goods industries. The term is a rather
broad label for substances that are able to interfere with hormone receptors or
hormonal pathways in the cell. Endocrine disruptors have caused serious public
concern, because their interaction with the hormone system could potentially
wreak havoc with prenatal and early development and affect a wide variety of
organs. Theo Colborn, a researcher for the World Wildlife Fund, painted a bleak
picture of their effects at a 2001 meeting of the US Department of the
Interior: "... these chemicals can undermine the development of the
brain, and intelligence and behaviour, and the endocrine, immune and
reproductive systems. ... there is now a growing collection of studies
revealing that some of these chemicals can affect our children's ability to
learn, to socially integrate, to fend off disease and to reproduce"
(Colborn, 2001).
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However, as public fear mounted, the evidence for a
creeping epidemic caused by endocrine disruptors in the environment remained
elusive
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In fact, early observations on wild and laboratory animals showed that
some compounds that are able to interact with receptor molecules, in particular
with the oestrogen receptor, exert effects on the reproductive system of these
animals. These observations were accompanied by reports on the increasing
incidence of breast and prostate cancer and declining male fertility, and it
was only a matter of time before the press took up the issue and parents became
concerned about this slow poisoning of their children. However, as public fear
mounted, the evidence for a creeping epidemic caused by endocrine disruptors in
the environment remained elusive. Although most scientists now acknowledge that
many substances can have an effect on the human endocrine system, more recent
analysis has shown that many of the claims about health effects were either
exaggerated or based on flawed analysis of observations. As Stephen H. Safe,
Professor of Veterinary Physiology and Pharmacology and of Biochemistry and
Biophysics at Texas A&M University (College Station, TX, USA) put it:
"The hypothesis is okay, but we don't even have a problem."
The scientific chapter of the endocrine disruptor story began in the
early 1990s with a 'hypothesis' article in The Lancet in which Richard
M. Sharpe from the MRC Reproductive Unit at the University of Edinburgh, UK,
and Niels E. Skakkebaek from the Department of Growth and Reproduction at the
University of Copenhagen, Denmark, wrote, "exposure to exogenous
oestrogens, ... during foetal and neonatal life can lead to an increase in
reproductive disorders" (Sharpe & Skakkebaek,
1993). On the basis of a meta-analysis of more than 60 studies
published between 1940 and 1990, they suggested that abnormalities in the
development of male sex organs and a 50% decline in sperm count could be
attributed to exposure to oestrogens in utero. The finding that the
prescription of an artificial oestrogen, diethylstilboestrol, for pregnant
women from the 1940s to the 1970s had caused an increased rate of cervical
cancer among the daughters of these women further supported Sharpe and
Skakkebaek's hypothesis, and the fear that men could also be affected did not
seem so far-fetched.
Observation of wildlife also provided evidence for the effects of
endocrine disruptors on reproductive health. Various publications described how
chemicals suspected to have endocrine-disrupting effects, including DDT,
dioxins, polychlorinated biphenyls (PCBs), which are all banned, and various
pesticides and fungicides, caused a wide range of reproductive disorders and
deformities of sexual organs among wild animals in polluted areas. Nonylphenol,
a degradation product from many detergents, herbicides, spermicides and
cosmetics, has been shown to cause imposex in oysters, which is a
pseudo-hermaphroditic condition in which females acquire male sex
characteristics (Nice et al, 2003).
Scientists in the UK found that oestrogenic compounds in human and agricultural
wastewater triggered the feminization of male fish in British lakes and rivers.
Else-where, US scientists found that female mosquito fish in Florida exposed to
pulp-mill effluent developed a gonopodium, an organ normally found only in
males. Similarly, male alligators in various contaminated lakes in Florida
suffered from phallus deformations and an impaired immune system. Half of male
carp caught in the Tama River in Japan were found to produce unusually large
amounts of the yolk precursor protein vitellogenin, specific to female
fish.
In 1996, Colborn, together with science writers Dianne Dumanoski and
John Peterson Myers, compiled these observations into the book Our Stolen
Future and drew a straight line between the effects observed in wild
animals and human health effects, including breast and prostate cancer and
decreasing male fertility caused by decreasing sperm counts, cryptorchidism
(where one or both testicles fail to descend from the body) and hypospadias
(deformation of the phallus). Often compared to Rachel Carson's Silent
Spring, Colborn's book had an enormous impact on public opinion and
triggered intense media coverage about the suspected epidemic of cancers and
male infertility. The media obtained further ammunition when Fred vom Saal and
co-workers at the University of Missouri (Columbia, MO, USA) showed that
bisphenol A (BPA), a commonly used compound found in many plastics, caused
abnormal prostate growth and decreased sperm production in rats at doses far
lower than those considered to be safe (Nagel et al,
1997; vom Saal et al, 1998).
Patricia Hunt at Case Western Reserve University (Cleveland, OH, USA) observed
that BPA caused severe aberrations of the meiotic cell division in mouse
oocytes in up to 40% of all cases (Hunt et al,
2003). Although industrial and academic researchers have so far
failed to reproduce vom Saal's findings, his work has become the main argument
for public health advocates who seek to ban chemicals such as BPA because they
can exert their toxic effects at extremely low doses.
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In fact, a series of studies that closely
investigated the original publications claiming an increase in breast and
prostate cancer and a decline in male fertility found that this is not
so
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The political reaction to these reports was swift, particularly in the
USA. The US Environmental Protection Agency (EPA) convened two workshops in
1995 to make recommendations for research into the health threat of endocrine
disruptors, including their effects on reproductive, neurological and
immunological function and carcinogenic activity. In 1996, the US Congress
amended the Food Quality Protection Act and the Safe Drinking Water Act to
require the testing of food-use pesticides and drinking water contaminants for
endocrine activity, which mandated the EPA to screen up to 70,000 chemicals
regulated under the Toxic Substances Control Act for endocrine-disruptive
effects. In 1999, the EPA launched the Endocrine Disruptor Screening Program
(EDSP) and is now developing animal tests and other assays to screen for
hormone activity. In Japan, the Ministry of the Environment decided to start
risk assessment studies on more than 40 substances suspected to have
endocrine-disrupting effects (Iguchi et al,
2002). On 29 October 2003, the European Commission proposed a new
regulatory framework for all chemicals manufactured or imported in quantities
of more than a tonne per year. Among the chemicals labelled as being of 'very
high concern' that require authorization for particular use are substances that
could cause reproductive damage or affect fetal development—in other
words, endocrine disruptors.
The only problem is that nobody actually knows whether the levels of
endocrine disruptors in the environment are a threat to public health.
"The so-called epidemic of endocrine diseases remains to be
established," said Raphael J. Witorsch, Professor of Physiology at
Virginia Commonwealth University in Richmond, VA, USA. A working group,
convened by the Royal Society of London, UK, that investigated the health
threat of endocrine- disrupting chemicals (EDCs) came to the same conclusion:
"whilst high levels of exposure to some EDCs could theoretically increase
the risk of such disorders, no direct evidence is available at present"
(The Royal Society, 2000). Richard Sharpe, one of
the original authors of the endocrine disruptor hypothesis, also acknowledged
that "the threat [to human health] is minimal." In fact, a series
of studies that closely investigated the original publications claiming an
increase in breast and prostate cancer and a decline in male fertility found
that this is not so. "We now know that this is absolutely not
true," Safe said about health advocates who warn that endocrine
disruptors could cause a worldwide epidemic of disorders and diseases.
According to Witorsch, many of the original epidemiological analyses were
flawed and lacked confounding factors.
In addition, large-scale studies among elderly women in the USA and the
UK showed that the increase in breast and cervical cancer was caused mainly by
hormone replacement therapy for post-menopausal women (Brower, 2003) rather than hormonally active compounds in the
environment. In fact, many of the chemicals under suspicion bind only weakly to
the oestrogen receptor and it is not clear whether they have an estrogenic,
anti-estrogenic or anti-androgenic effect. Furthermore, critics maintain that
EDCs have to compete with more effectively binding natural oestrogens that are
abundant in the diet, in medicines and in contraceptives at much higher
concentrations. "In terms of magnitude and extent, all such exposures to
so-called endocrine disruptors are dwarfed by the extensive use of oral
contraceptives and estrogens for the treatment of menopausal and
post-menopausal disorders. Also, the exposure to hormonally active xenobiotics
is virtually insignificant when compared with the intake of the phytoestrogens
that are present in food and beverages," commented Robert Nilsson,
Professor of Toxicology at Stockholm University, Sweden (Nilsson, 2000). "So we've got all these
[phytohormones] out there in the diet," Safe concluded, but "my
scepticism is how could small concentrations [of other chemicals] in the
environment be a problem?"
Equally, the low-dose effects that vom Saal observed in mice have come
under criticism. "I remain completely unconvinced by the low-dose
studies. ... How does BPA in Fred vom Saal's study induce an effect at
concentrations at which we know that it doesn't bind to the oestrogen
receptor?" Sharpe said. "I want to see that these effects can lead
to disorders that are directly related to human health issues." But
Sharpe still sees a potential problem with compounds that act elsewhere in the
signalling pathway and modify the internal balance of hormones. "If you
alter the endogenous hormonal milieu, then you get a disease," he said.
"I have no problem with understanding that chemicals that have that
ability can cause health problems."
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... critics maintain that endocrine-disrupting
chemicals have to compete with more effectively binding natural oestrogens that
are abundant in the diet, in medicines and in contraceptives at much higher
concentrations
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Indeed, the evidence of detrimental effects of endocrine disruptors in
animals, particularly for aquatic organisms, is quite convincing, Sharpe
maintained. He cited the example of TBT (tributyltin), widely used in ship
paint. The chemical does not bind to a hormone receptor but modulates the
endogenous hormonal milieu in mussels elsewhere to cause imposex. Consequently,
as the human fetus is "kind of an aquatic organism," as Sharpe put
it, such chemicals could potentially impair prenatal development and cause
effects later in life. But "humans are different from fish," Safe
countered, and he questioned the sense of extrapolating observations made in
wild or laboratory animals to humans, who often have very different hormonal
metabolisms. "There isn't a single chemical that doesn't have an
effect," he said, but "what are these animal studies telling
us?" Witorsch agreed that making such assumptions is like "shooting
from the hip". "To judge in utero effects in rodents and try
to extrapolate them to humans has to be done with caution," he said.
"An observation doesn't mean that you should ban a substance and a lack
of observation doesn't necessarily mean that it is safe."
For that very reason, many experts think that broad screening programmes
based on animal testing, such as the EDSP, do not make much sense.
"They're going to find some [chemicals] that are active and some that are
inactive—so what?" Safe said, adding, "Is that the best use
of taxpayer's money?" Nevertheless, the EPA has devised new testing
guidelines that should address the subtleties of endocrine action better. Their
new multi-generation tests investigate several endpoints relevant to
reproductive performance, such as the female oestrous cycle, various parameters
on sperm count and quality in parental and F1 generations, and the
age at puberty in the F1 generation; they also include pathological
tests for the impaired development of various organs. However, Witorsch remains
unconvinced. "I'm not enthralled by the EDSP. ... These tests have been
designed without appreciation of the complexity of the endocrine system,"
he said, adding, "I'm as underwhelmed with the EU approach as I am with
the EDSP." Furthermore, as most of the testing and research concentrates
on oestrogen and thyroid receptors, Witorsch thinks that it misses other
equally important players in the endocrine system. "One of the benchmarks
of naïveté is to totally ignore glucocorticoids and the
physiological role of stress response," he said.
Sharpe is equally unconvinced by broad screening programmes and would
rather put the focus on good epidemiology. "We need better exposure data.
And that's the area where we have the weakest information," he said.
Starting with chemicals for which there is genuine concern about cancer and
male reproductive disorders, investigating their exposure particularly during
pregnancy and then looking at their activity "would be a hell of a lot
cheaper. ... It is possible that there are compounds out there that [modulate
the endogenous system] and that they are very potent. But you can't find those
with a screening system." The Royal Society's working group came to the
same conclusion: "The report emphasises the difficulties of making
generalised assumptions based on isolated experiments and the problems of
developing policy in areas in which scientific understanding is still being
developed. ... In order to improve our understanding of the relationship of
EDCs to health and disease, further investigation is needed."
Instead of "fishing expeditions", Witorsch thus advocates
"good mechanistic research" to gain more knowledge about hormonal
action and physiological pathways before making any further assumptions about
potential health problems. "We can only accept at this particular stage
that it is a mechanism that we have to explore more," he said. In the
light of public fears—unfounded or not—it is certainly necessary to
shift the debate about the human health dangers of endocrine disruptors to a
more factual level. And that includes scientists. "The important thing is
not to listen to what I say or what vom Saal says but to look at the
facts," Safe said, "And then the question you should ask is 'is
there anything?'"
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References
Brower V ( 2003) A second chance for hormone replacement therapy? EMBO rep 4: 1112–1115 | Article | PubMed | ChemPort |
Colborn T ( 2001) The path before us: environmental stewardship in the 21st century. www.worldwildlife.org/toxics/progareas/ed/doi_speech.pdf"
Hunt PA, Koehler KE, Susiarjo M, Hodges CA, Ilagan A, Voigt RC, Thomas S, Thomas BF, Hassold TJ ( 2003) Bisphenol A exposure causes meiotic aneuploidy in the female mouse. Curr Biol 13: 546–553 | Article | PubMed | ChemPort |
Iguchi T, Sumi M, Tanabe S ( 2002) Endocrine disruptor issues in Japan. Congen Anom 42: 106–119 | ChemPort |
Nagel SC, vom Saal FS, Thayer KA, Dhar MG, Boechler M, Welshons WV ( 1997) Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol. Environ Health Perspect 105: 70–76 | PubMed | ChemPort |
Nice HE, Morritt D, Crane M, Thorndyke M ( 2003) Long-term and transgenerational effects of nonylphenol exposure at a key stage in the development of Crassostrea gigas. Possible endocrine disruption? Mar Ecol Prog Ser 256: 293–300 | ChemPort |
Nilsson R ( 2000) Endocrine modulators in the food chain and environment. Toxicol Pathol 28: 420–431 | PubMed | ChemPort |
Sharpe RM, Skakkebaek NE ( 1993) Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 341: 1392–1395 | Article | PubMed | ChemPort |
The Royal Society ( 2000) Endocrine disrupting chemicals www.royalsoc.ac.uk/files/statfiles/document-111.pdf .
Vom Saal FS, Cooke PS, Buchanan DL, Palanza P, Thayer KA, Nagel SC, Parmigiani S, Welshons WV ( 1998) A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behaviour. Toxicol Indust Health 14: 239–260 | ChemPort |
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