http://www.cosmosmagazine.com/node/3418/full
Be Well.
David
Demasculinisation and other side effects
Cosmos Online
Concrete jungles are not the only part of our environment that is man made. There are also thousands of man-made chemicals and this chemical environment is a vast, unchecked experiment on human health.
In 2005, Shanna Swan and her colleagues discovered that the phthalates in plastic baby products and toys led to a variety of penile disorders, including reduced size.
Credit: iStockphoto
We are all unwittingly participating in a massive experiment without our consent. We are exposed to hundreds (and perhaps thousands) of man-made chemicals whose impacts on our health have barely been considered. But increasingly we are learning that many can threaten human health.
Of particular concern are those chemicals that modify how our hormones function and the multiplicity of complex signals that our bodies need to function properly. These chemicals are known as endocrine disruptors, and only now are we becoming aware of their profound influence on how we feel, how we function, how healthy we are, and how little we know about them.
Rachel Carson stirred the first notable misgivings about our contaminated environment in her 1962 summons to action, Silent Spring. She provoked us to listen to her sentinels: "…On the mornings that had once throbbed with the dawn chorus of scores of bird voices there was now no sound; only silence lay over the fields and woods and marsh."
Carson wrote about wildlife, where we saw the earliest clues to what we had wrought by contaminating our environment. Humans are not exempt from these consequences.
Our current understanding of how these chemicals can alter human health began with the discovery of the disastrous impacts of a drug, diethylstilbestrol, or DES. The FDA approved DES for the prevention of miscarriage in 1947.
It was marketed worldwide despite a well-done clinical study showing it was therapeutically ineffective. It proved to be a biological time bomb. Daughters of women who had been prescribed DES appeared to be healthy.
But, after undergoing the hormonal changes of adolescence, a majority of those who had been exposed early in pregnancy developed a multitude of adverse effects. They showed abnormalities of the reproductive tract; they had problems conceiving and, if they succeeded in becoming pregnant, they were far less likely to carry their pregnancy to term.
Most seriously, and fortunately far less often, they developed a rare form of vaginal cancer. New evidence is now suggesting that these reproductive problems can also affect the third generation.
DES is a synthetic estrogen. Other estrogenic chemicals were already known to pervade the environment; they had been targeted as the source of the eggshell thinning that had decimated bird populations such as the bald eagle.
It was a natural step to begin searching for other kinds of effects. They were not hard to find. And they provoked intense concern about human health.
These concerns culminated in a conference, held in the Wingspread Conference Centre in Wisconsin, in 1991. Its theme became the impetus for what became a prodigious research effort: chemically induced alterations in sexual development: the wildlife/human connection.
The Wingspread consensus statement listed the suspect chemicals. It described the wildlife populations that had been afflicted by chemical exposures; it linked these effects to human health by showing how we, too, are exposed; it called for remediation to prevent disorders in human populations.
The Wingspan consensus also conceived the term, 'endocrine disruption', to describe the mechanisms by which these chemicals acted. They act by mimicking and displacing natural hormones, by antagonizing their effects, by changing how the body synthesizes them, by changing their concentrations in the body.
Wingspread alerted the scientific community. But the lay public remained largely unaware of these issues until the publication in 1996 of a seminal book that was to become an international best seller: Our Stolen Future, by Theo Colborn, Diane Dumanoski and John Peterson Myers.
Our Stolen Future, now translated into 20 languages, aroused a silent public, led to U.S. Congressional hearings and increased funding for research and transformed the science of toxicology.
What is new about this new science? Endocrine disruptors are stealth chemicals. Unlike smoking, or DES, these chemicals are silent; they enter our bodies without our knowledge. Exposure to many of these chemicals is ubiquitous; the Centers for Disease Controls now tests regularly for nearly 150 chemicals and a majority are detectable in us.
Their effects are subtle and careful (and expensive) studies are required to demonstrate these effects. The FDA withdrew approval of DES by pregnant women on the basis of only eight cases of vaginal cancer in young women. Demonstrating effects of environmental endocrine disruptors requires far larger studies and much more subtle endpoints.
We are only now beginning to appreciate how broadly men and women differ in how they develop, in their patterns of disease and responses to treatment. Many of these differences are tied to innate hormones and other chemical signals within the body.
So it should not surprise us that endocrine disrupting chemicals can be expected to exert their effects differently in males and females. This understanding guides our current research and has led us to choose measures for our studies that are sensitive to these differences.
This current research is often guided by findings in rodents (unlike DES research where animal studies followed the discovery of the human catastrophe). In rodents we can identify subtle changes to the target organ—the reproductive tract, the brain—but in humans we must rely on what we can measure without inflicting physical harm.
And, even with animals, maleness and femaleness are not just about the genitals. Hormonal differences pervade our physiology; differences in thyroid function, immune function and, of course, behaviour.
Consider a single class of endocrine disruptors: the phthalate esters. Phthalates are produced in prodigious quantities, on the order of several millions of kilograms annually. They make plastic soft and serve as plasticizers for polyvinyl chloride products ranging from medical tubing to shower curtains.
They are found in children's toys and teething rings (now banned in the EU and U.S.), cosmetics, enteric coatings for medications, vinyl flooring and wallpaper, food packaging and many other products. The exposure sources include food, drinking water, and house dust.
Phthalates are used as 'inert' ingredients in pesticide formulations. Toxic dumps are contaminated by phthalates and they find their way into aquatic environments.
Phthalate comprise a large chemical class, and some are more toxic than others. Those of most concern have been shown to be anti-androgenic; that is, they have the potential to interfere with or reduce testosterone.
If you administer phthalates to a pregnant rodent, the male offspring exhibit a variety of reproductive tract anomalies such as undescended testes, a cleft phallus (hypospadias), and indices of feminisation such as retained nipples.
They also show a shortened anogenital distance, the distance between the anus and the genitals. Toxicologists have traditionally used this measure to decide on the sex of newborn pups, since it is twice as long in males as in females.
As a group these changes induced by prenatal phthalate exposure have been termed the 'phthalate syndrome', which is produced by the inhibition of testosterone secretion by the foetal testis during a critical developmental period.
The usual testing paradigms in toxicology administer high doses of chemicals so that it is possible to identify adverse effects using small numbers of animals. Moreover, these chemicals are tested one at a time, and by a single route of exposure (usually oral).
We are recognising that humans are exposed to a mixture of chemicals, for example more than a dozen phthalates and their breakdown products (metabolites), and that these enter our bodies orally, dermally, by inhalation and even intravenously (for example, newborns in the neonatal intensive care nursery). These exposures can act together, producing effects that can be missed when they are examined singly.
Until recently, phthalates were not considered a threat to human health because we are exposed to much lower levels than those used in animal laboratory tests.
Not until 2005, that is. In an article now considered a landmark publication, one of us, Shanna Swan, showed that boys born to women with higher levels of phthalate metabolites in their urine exhibited shorter anogenital distances and reduced penile size.
The result aroused keen worldwide interest because these women had only been exposed to ordinary environmental levels of phthalates. It triggered a new burst of research. The findings were confirmed and extended.
It led governments and regulatory agencies to ban phthalates in toys and teething rings. The Australian government banned children's toys that contain over 1% diethylhexyl phthalate in January 2010.
Testosterone doesn't just govern genital structure. It also governs brain anatomy. Male brains differ from female brains. The differences arise from the actions of foetal testosterone.
It is the hormone that moulds and organises the brain, and this brain structure has been clearly shown to affect behaviour. Testosterone is the main source of differences between how men and women behave. Its effects can be seen from magnetic resonance images of male and female brains.
If male and female brains are different, should we expect to see maternal phthalate levels related to differences in children's behaviour? We posed that question to the same population of women whose children contributed the anogenital distance data. This time, we asked the women about their child's behaviour.
We chose a behaviour that we know differs between boys and girls: how they play and what they choose to play with. We asked that question by using a standardised questionnaire called the Preschool Activities Inventory.
It lists items such as preferred toys (trucks versus dolls, for example), modes of play (wrestling versus playing quietly), and other activities that are sex-linked.
In our 2009 article, published in International Journal of Andrology, we showed that higher phthalate concentrations in the mother's urine predicted less masculine play patterns in their boys.
It demonstrated that the brain, like the genitals, can be transformed by phthalates. This is only the beginning of the story. Phthalates are undergoing more study because we still don't know about the full scope of their effects.
And we have embarked on a new research program, this time devoted to Bisphenol A (BPA). It is a plastic ingredient found in baby bottles, can linings, and many other products. We are all exposed to BPA, and carry it in our bodies.
Bisphenol A has been banned from baby bottles in Canada. The United States Food and Drug Administration, originally lethargic about any action, has now been induced to more carefully assess the evidence pointing to its health threats. Many Australians would like to see their own government out in front on the issue.
Our own interests lie in how bisphenol A might alter brain development. It is an estrogen, like DES (as was demonstrated for both chemicals by Sir Charles Dodds in the 1930s). We are asking the question in both rats and humans. And we are starting to examine bisphenol A in a mixture with phthalates and other chemicals.
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