Endocrine Disruptors (and other chemicals): A cause without a disease
Breithaupt, Holger. 2004. A Cause Without A Disease, EMBO Reports 5(1):16
18.
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
Endocrine disruptors - or "gender benders" as they are often referred to by the
public齻ave 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).
However, as public fear mounted, the evidence for a creeping epidemic caused by
endocrine disruptors in the environment remained elusive. 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 and
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.
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 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齺n
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." ... 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 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鑸o 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 na1vet 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鑵nfounded or not齺t 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?'"
References
Brower, V. (2003) A second chance for hormone replacement therapy? EMBO rep 4:
1112-1115
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. Current Biology 13: 546-553
Iguchi T, Sumi M, Tanabe S. (2002) Endocrine disruptor issues in Japan.
Congen Anom 42: 106-119
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.
Environmental Health Perspectives 105: 70-76
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Nilsson, R-O. 2000, Endocrine Modulators in the Food Chain and Environment,
Toxicology Pathology, 28(3):420 431, May-June.
Abstract:
Recently, considerable attention has been focused on certain environmental
contaminants "endocrine disruptors" of industrial origin that may mimic the
action of sex hormones. Natural compounds and their effects on other types of
hormonal activity leg. on adrenal or thyroid function) have for some reason not
provoked similar attention. As exemplified by tributyltin and certain
bioaccumulating chlorinated compounds. available evidence indicates that
"endocrine disruption" caused by xenobiotics is primarily an ecotoxicologic
problem. In mammals, certain phenylmethyl substituted siloxanes have been found
to be by far the most potent endocrine disrupters among various synthetic
xenobiotics. Oh the other hand, it has not been possible to scientifically
substantiate either certain alarming reports of powerful synergistic effects
between chlorinated pesticides or the alleged adverse effects on the male
reproductive tract in rodents (induced by alkylphenols and plasticizers at
extremely low exposures).
Whereas there is compelling evidence that estrogens in certain foods and herbal
medicines can induce hormonal changes in women as well as oven toxicity in men,
existing data are insufficient to support a causal relationship between exposure
of the general human population to nonpharmaceutical industrial chemicals and
adverse effects operating via the endocrine system. Moreover, 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 treatment
of menopausal and postmenopausal 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, and it is even more insignificant when compared with certain herbal
potions used in "alternative medicine." Furthermore, while there has been much
concern about negligible exposures to xenobiotics with weak hormonelike
activities, the potent endocrine disrupter licorice is freely given to children.
Long term exposure to this substance induces severe toxic symptoms of mineral
corticoid hormone imbalance.
Although exposures to xenobiotics: and many natural compounds occur by identical
routes of administration and may contribute to the same toxicological end point,
they are, regrettably, judged by completely different standards. As is the case
with all other chemicals, rational risk assessment and risk management of man
made and natural endocrine modulators must be based on rbe mode of action and
dose response relationships. Such end points as the induction of reproductive
developmental effects, cancer, etc, relating to actual exposures must also be
taken into consideration.
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Beier, R.C. 1990. Natural Pesticides and Bioactive Components In Foods,
Review of Environmental Contamination and Toxicology, 113:47 137.
In this review, some common food plants and their toxic or otherwise bioactive
components and mycotoxin contaminants have been considered. Crucifers contain
naturally occurring components that are goitrogenic, resulting from the combined
action of allyl isothiocyanate, goitrin, and thiocyanate. Although crucifers may
provide some protection from cancer when taken prior to a carcinogen, when taken
after a carcinogen they act as promoters of carcinogenesis.
Herbs contain many biologically active components, with more than 20% of the
commercially prepared human drugs coming from these plants. Onion and garlic
juices can help to prevent the rise of serum cholesterol. Most herbs used in
treatments may have many natural constituents that act oppositely from their
intended use. Some herbs like Bishop's week seed contain carcinogens, and many
contain pyrrolizidine alkaloids that can cause cirrhosis of the liver. The
general phytoalexin response in plants (including potatoes, tomatoes, peppers,
eggplant, celery, and sweet potatoes) induced by external stimuli can increase
the concentrations of toxic chemical constituents in those plants.
In potatoes, two major indigenous compounds are alpha solanine and alpha
chaconine, which are human plasma cholinesterase inhibitors and teratogens in
animals. Because of its toxicity, the potato variety Lenape was withdrawn from
the market. Celery, parsley, and parsnips contain the linear furanocoumarin
phytoalexins psoralen, bergapten, and xanthotoxin that can cause
photosensitization and also are photomutagenic and photocarcinogenic. Celery
field workers and handlers continually have photosensitization problems as a
result of these indigenous celery furanocoumarins. A new celery cultivar (a
result of plant breeding to produce a more pest resistant variety) was
responsible for significant incidences of phytophotodermatitis of grocery
employees.
Since there is no regulatory agency or body designated to oversee potential
toxicological issues associated with naturally occurring toxicants,
photodermatitis continues to occur from celery exposure. Sweet potatoes contain
phytoalexins that can cause lung edema and are hepatotoxic to mice. At least one
of these, 4 ipomeanol, can cause extensive lung clara cell necrosis and can
increase the severity of pneumonia in mice. Some phytoalexins in sweet potatoes
are hepatotoxic and nephrotoxic to mice.
The common mushroom Agaricus bisporus contains benzyl alcohol as its most
abundant volatile, and A. bisporus and Gyromitra esculenta both contain
hydrazine analogues. Mycotoxins are found in corn, cottonseed, fruits, grains,
grain sorghums, and nuts (especially peanuts); therefore, they also occur in
apple juice, bread, peanut butter, and other products made from contaminated
starting materials.
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Doerge, Daniel R. and Daniel M. Sheehan. 2002. Goitrogenic and Estrogenic
Activity of Soy Isoflavones, Environmental Health Perspectives
Supplements 110(S3): 349 353, June.
Abstract
Soy is known to produce estrogenic isoflavones. Here, we briefly review the
evidence for binding of isoflavones to the estrogen receptor, in vivo
estrogenicity and developmental toxicity, and estrogen developmental
carcinogenesis in rats. Genistein, the major soy isoflavone, also has a frank
estrogenic effect in women. We then focus on evidence from animal and human
studies suggesting a link between soy consumption and goiter, an activity
independent of estrogenicity. Iodine deficiency greatly increases soy
antithyroid effects, whereas iodine supplementation is protective. Thus, soy
effects on the thyroid involve the critical relationship between iodine status
and thyroid function. In rats consuming genistein fortified diets, genistein was
measured in the thyroid at levels that produced dose dependent and significant
inactivation of rat and human thyroid peroxidase (TPO) in vitro. Furthermore,
rat TPO activity was dose dependently reduced by up to 80%. Although these
effects are clear and reproducible, other measures of thyroid function in vivo
(serum levels of triiodothyronine, thyroxine, and thyroid stimulating hormone;
thyroid weight; and thyroid histopathology) were all normal. Additional factors
appear necessary for soy to cause overt thyroid toxicity. These clearly include
iodine deficiency but may also include additional soy components, other defects
of hormone synthesis, or additional goitrogenic dietary factors. Although safety
testing of natural products, including soy products, is not required, the
possibility that widely consumed soy products may cause harm in the human
population via either or both estrogenic and goitrogenic activities is of
concern. Rigorous, high quality experimental and human research into soy
toxicity is the best way to address these concerns. Similar studies in wildlife
populations are also appropriate.
Key words: estrogen toxicity, estrogenicity, genistein, isoflavones, mass
spectrometry, soy, thyroid peroxidase, thyroid toxicity. Environ Health Perspect
110(suppl 3):349 353 (2002).
http://ehpnet1.niehs.nih.gov/docs/2002/suppl 3/349 353doerge/abstract.html.