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Authors: Susan Freinkel

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As Colborn would have predicted, the devil was in the timing of exposure. The EPA studies used relatively high doses of phthalates, but other animal studies have found that even very small amounts of DEHP can reduce sperm production, provoke early puberty, and have other subtle warping effects if administered during critical periods of development.
That's when being a little plastic can be a big problem.

The effects in rats are mirrored by broad trends in human reproductive health. Epidemiologists have charted rising rates of male infertility, testicular cancer, decreased testosterone levels, and diminished sperm quality in many Western countries. The number of boys born with hypospadias has increased significantly since the late 1960s, according to some studies (though not all), and the number born with undescended testicles has also risen during the same period.
Meanwhile, several studies have reported that infertility rates among women are on the rise. During this same period, humans' exposure to DEHP and other phthalates has undoubtedly increased, given their steadily rising production and use. The result is that at least 80 percent of Americans—of all ages and races, from city dwellers to residents of remote rural towns—now carry measurable traces of DEHP and other phthalates in their bodies, according to biomonitoring studies by the Centers for Disease Control.
Researchers have detected phthalates in blood, urine, saliva, breast milk, and amniotic fluid, which means people are being exposed to the chemicals at all stages of life, starting in utero.
The chemicals pass quickly through our bodies, but we are exposed on such an ongoing basis that the overall amounts in our systems don't change dramatically over time. Our cells are under continual low-level chemical assault.

None of us are exposed to DEHP at the levels that produced those devastating results in fetal rats.
Still, many of us are taking in more than the daily limit advised by the EPA—a threshold set in 1986 and based on studies done well before the concept of endocrine disruption was on anybody's radar.
Some of the people with the highest levels are the very ones who most need to steer clear of hormonal disrupters, such as children and women of childbearing age.
Studies consistently find that children harbor higher phthalate levels than adults, which may be due to several factors, including that they metabolize chemicals more slowly; eat, drink, and breathe more per pound of body weight; and are more likely to put vinyl toys in their mouths. (One researcher told me she once found a particularly noxious-smelling vinyl bath book for babies called
Splish-Splash Jesus.
)
Such findings led an expert panel convened by the National Toxicology Program in 2006 to conclude that there were grounds for "concern" that DEHP exposure can affect the reproductive development of baby boys under the age of one.

But the group that seems to be at greatest risk are newborns undergoing treatment in a NICU.
Studies show that a baby like Amy who is hooked up to IV bags and tubing for weeks at a time may end up absorbing doses of DEHP a hundred to a thousand times higher than the general population. The chemical hit will be even larger if she gets blood transfusions or if she later has to be connected to a heart-lung machine that circulates and oxygenates the blood in her body. The machines are commonly used for babies with severe respiratory problems or those who have undergone heart surgery. They're lifesavers, but they also deliver huge amounts of DEHP, said Naomi Luban, a pediatric hematologist at Children's National Medical Center who works with Short and has long been concerned about the risks of plasticizers. The transfused blood is laced with DEHP from blood bags, but there's another problem as well. As the blood circulates through the heart-lung device, it flows through several dozen feet of plastic tubing and a plastic membrane—all leaching DEHP. A really sick baby getting that kind of intensive treatment can wind up with a cumulative exposure twenty times higher than the level deemed safe for human intake.
(Indeed, people of any age undergoing procedures such as kidney dialysis and blood transfusions are at risk of getting a significant blast of DEHP.)

Because these newborns are underdeveloped, they may be especially vulnerable to the chemical's hormonal impacts.
The cellular barriers to their brains and organs are more easily permeated. What's more, they don't yet have the capacity of adults or even of older children to clear the chemical from their systems, meaning it circulates for a longer time, increasing the potential for damage.

As the CDC has pointed out, the mere presence of DEHP, or any chemical, in someone's blood or urine does not mean it is a health hazard. The big, and difficult, question is whether the small amounts to which we are all regularly exposed are sufficient to affect
some
people's health. We may all be a little plastic, but that doesn't mean we are all affected in the same way. Some individuals, such as NICU babies, may be at greater risk because of the amounts they take in or their stage of life.
Given that researchers can't subject humans to the kinds of tests done with lab rats to pinpoint the conditions that cause adverse effects, it's not unreasonable to view ourselves as subjects of a vast, uncontrolled experiment. But we are not entirely blind as we journey through this vast plastic laboratory called modern life. Epidemiological studies—surveys of large groups of people—offer an indirect way to gather evidence. Shanna Swan, a reproductive epidemiologist at the University of Rochester School of Medicine and Dentistry, has conducted several such studies, and her findings suggest that some of us do pay a price for being a little plastic.

In one study, she measured phthalate levels in 134 pregnant women and then later closely examined the genitalia of their baby sons. She found the sons of mothers with the highest phthalate levels had subtle but unmistakable symptoms echoing the phthalate syndrome seen in rats. They were more likely to have undescended testicles, a smaller penis, and a shorter distance between the base of the penis and the anus, the measurement that in the rat studies was considered a hallmark of decreased fetal testosterone levels.
"These babies had no abnormalities that a clinician would recognize," Swan emphasized. But given the long-term effects on exposed rats, she considered even these subtle changes a worrisome collection of symptoms that could affect the boys' fertility later in life.

Swan then decided to look at how else an antiandrogen might affect a developing fetus. The male reproductive tract isn't the only body system touched by testosterone. Like estrogen, the hormone circulates throughout the body, affecting metabolism, growth, behavior, and cognition, as well as the actions of other hormones, in both boys and girls. "The brain is the largest sex organ," Swan likes to say. "It also is developed under the influence of testosterone."

Normally, testosterone levels in the brain surge during certain critical points of development, which is thought to play an essential role in the process of sexual differentiation. Studies have shown that when pregnant rats are exposed to drugs known to block that hormonal surge, their male offspring don't engage in the same kind of rough-and-tumble play as unexposed pups.

Taking her cue from those findings, Swan went back to the same group of parents and children she'd studied before. The kids were now in preschool. For this study, she had the parents fill out a detailed questionnaire about how their children play. She asked them to rate how frequently their child played with toys like dolls or trucks, how often the child set up house or pretended to fight. The boys with the highest fetal exposure to the phthalates DEHP and DBP had the lowest scores on typical boy play, such as pretending to shoot a gun. They were also more likely to prefer gender-neutral play, such as working on puzzles.
The girls showed no effect.

It was the kind of finding headline writers love. "Common Chem­icals Make Boys Soft," one Australian paper declared. But Swan wasn't reporting a nifty solution to macho aggression. She was describing a subtle shift in the hard-wiring of the boys' brains so that they played in "less typically masculine" ways. It was a small effect but one with potentially profound implications, given that testosterone, estrogen, and other hormones shape the many differences in how male and female brains develop and process the world.

Both studies need to be replicated. But having found that phthalates can affect two very different body systems, Swan asked, "Why should we assume the effects are just limited to two? My concern is we are seeing changes throughout the body wherever testosterone matters, and that's many, many places."

Other epidemiological findings lend weight to her concerns. A variety of small studies have found an association between exposure to phthalates and obesity, early puberty, allergies, ADD, and altered thyroid function—all conditions that could plausibly be related to hormonal disruptions.
Most of the studies have focused on boys. But a handful suggest that girls may also be affected by the drops in testosterone or by some as-yet-undescribed effect on their estrogen levels. Some researchers have postulated that the chemical can suppress estrogen production in females, said Swan. "We're all struggling to figure out what's going on with females. It's difficult because the female reproductive system is invisible. The males are easier because it all hangs out." Still, a small number of epidemiological studies have found correlations between phthalate levels and endometriosis, miscarriage, uterine fibroids, and premature breast development.

DEHP's hormonal effects may not be the only problem. A 2010 study suggested that in very young infants, the chemical may interfere with the cellular systems involved in controlling inflammation, part of the body's method of fighting infection.
Other studies have linked DEHP with immune system and respiratory problems and have continued to raise red flags about toxicity to the liver, especially in premature babies who are being exposed due to their treatment in NICUs. German researchers showed that babies in intensive care who received fluids from IV bags containing DEHP were more likely to develop a particular type of liver problem than those whose IV bags didn't contain the chemical.

This all sounds like pretty strong evidence, right? And yet science rarely delivers straight slam dunks. Consider just one endpoint thought to be affected by DEHP: cells in the testes that secrete testosterone. Rat studies have repeatedly found that DEHP damages those cells. But rats are the most phthalate-sensitive of all species tested. Recent primate studies involving young marmosets have found no such effect.
Does that mean primates—our closest relatives—aren't as sensitive to the chemical as rodents? Or were the marmosets past the age when they would have been vulnerable to the effects? Researchers are still debating the question.
Likewise, the epidemiological findings on sperm quality have been inconsistent: some studies show correlations with phthalate levels, some don't.

It's hard and expensive to mount the kinds of studies that can deliver clear-cut answers. For instance, Drs. Short and Luban have long wanted to do a study following babies who were heavily exposed to DEHP as a result of being on heart-lung machines. "If any population would have long-term reproductive effects, it would be those kids," said Short. "If the results came back negative, it would put all this stuff to rest." They did a small pilot study in which they found and tested eighteen teenagers who as infants had spent time in the NICU on the machines. None showed signs of any reproductive problems.
But it's impossible to draw any valid conclusions from a group that small. Statistically speaking, at least two hundred and fifty kids would have to be studied to get robust results. Short and Luban estimated it would take ten million dollars to track down and test that many survivors. They wrote up a proposal to do such a study, but neither the National Institutes of Health nor private industry was willing to make the investment. "That ten-million-dollar price tag was just prohibitive," said Short.

"But, boy, it would have been nice to have [the answers]," added Luban.

The continuing uncertainties are one reason why expert panels that have looked at DEHP and other phthalates have come to differing conclusions and also why nearly every research paper ends with the same mantra: more and better studies are needed.

One of the biggest gaps in research is the paucity of studies looking at the real world of chemical exposure. A person is not exposed to just a single chemical at a time; each day each of us encounters hundreds. And that chemical bombardment begins even before birth: a study by the organization Environmental Working Group found an average of two hundred industrial chemicals and pollutants in the umbilical-cord blood of ten newborns.
What's the cumulative effect? Researchers have only begun addressing that question. The early findings are cause for concern.

Earl Gray, the EPA researcher who identified phthalate syndrome, tested mixtures of phthalates in rats. He deliberately used low doses of each, well below amounts that could produce effects individually. Yet when he exposed male rats in utero to the mixtures, as many as 50 percent were born with hypospadias or other reproductive abnormalities. In combination, the chemicals were far more potent than they were individually, suggesting that compounds that act on the same hormonal pathways have an additive effect, he said.

Researchers say we need more of these kinds of studies, ones designed to mimic the real experience of human exposure. Swan and others want to see more research that focuses on pregnant women and children to gain a long-term picture of chemical effects rather than isolated snapshots. That's just what a recently begun study aims to do: the National Children's Study will follow a hundred thousand children across the United States from birth to the age of twenty-one in an effort to tease out environmental influences, including exposure to phthalates and bisphenol A, on health.

So if DEHP and other phthalates haven't been proven unsafe, does that mean they are safe?

The chemical industry, as might be expected, maintains they are. There is, after all, a $1.4 billion market in phthalates on the line. The American Chemistry Council's position, as one spokeswoman noted, is that "DEHP medical devices have been used for better than fifty years, and there hasn't been any verified evidence of harm to humans."
Even in the case of neonates, the group maintains, the benefits of treatment outweigh the risks posed by exposure.

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