In the 12th week of a human pregnancy, the momentous event of gender formation
begins, as X and Y chromosomes trigger biochemical reactions that shape male or
female organs. Estrogens carry the process forward in girls, while in boys, male
hormones called androgens do.
Now scientists have indications the process may be influenced from beyond the
womb, raising a fresh debate over industrial chemicals and safety. In rodent
experiments, common chemicals called phthalates, used in a wide variety of products
from toys to cosmetics to pills, can block the action of fetal androgens. The
result is what scientists call demasculinized effects in male offspring, ranging
from undescended testes at birth to low sperm counts and benign testicular tumors
later in life. "Phthalate syndrome," researchers call it.
Whether phthalates -- pronounced "thallets" -- might affect sexual
development in humans, too, is now a matter of hot dispute. Doses in the rodent
experiments were hundreds of times as high as the minute levels to which people
are exposed. However, last year, federal scientists found gene alterations in
the fetuses of pregnant rats that had been exposed to extremely low levels of
phthalates, levels no higher than the trace amounts detected in some humans.
Then this year, two direct links to humans were made. First, a small study
found that baby boys whose mothers had the greatest phthalate exposures while
pregnant were much more likely than other baby boys to have certain demasculinized
traits. And another small study found that 3-month-old boys exposed to higher
levels of phthalates through breast milk produced less testosterone than baby
boys exposed to lower levels of the chemicals.
Scientists are raising questions about phthalates at a time when male reproductive
disorders, including testicular cancer, appear to be on the rise in many countries.
Seeking an explanation, European endocrinologists have identified what some
see as a human counterpart to rodents' phthalate syndrome, one they call "testicular
dysgenesis syndrome." Some think it may be due in part to exposure to phthalates
and other chemicals that interfere with male sex hormones.
"We know abnormal development of the fetal testes underlies many of the
reproductive disorders we're seeing in men," says Richard Sharpe of the
University of Edinburgh in Scotland, a researcher on male reproduction. "We
do not know what's causing this, but we do know high doses of phthalates induce
parallel disorders in rats."
It isn't surprising to find traces of phthalates in human blood and urine,
because they are used so widely. Nearly five million metric tons of phthalates
are consumed by industry every year, 13 percent in the U.S. They are made from
petroleum byproducts and chemically known as esters, or compounds of organic
acid and alcohol. The common varieties with large molecules are used to plasticize,
or make pliable, otherwise rigid plastics -- such as polyvinyl chloride, known
as PVC -- in things like construction materials, clothing, toys and furnishings.
Small-molecule phthalates are used as solvents and in adhesives, waxes, inks,
cosmetics, insecticides and drugs.
Users and producers of phthalates say they are perfectly safe at the very low
levels to which humans are exposed. Phthalates are among the most widely studied
chemicals and have proved safe for more than 50 years, says Marian Stanley of
the American Chemistry Council, a trade association.
She says studies suggest primates, including humans, may be much less sensitive
to phthalates than are rodents. She cites a 2003 Japanese study of marmoset
monkeys exposed to phthalates as juveniles, which found no testicular effects
from high doses. The study was sponsored by the Japan Plasticizer Industry Association.
Scientists involved in a California regulatory review questioned the study and
maintained it didn't support the conclusion that humans are less sensitive to
phthalates than rodents are.
Ms. Stanley's conclusion: "There is no reliable evidence that any phthalate,
used as intended, has ever caused a health problem for a human."
The phthalate debate is part of the larger societal issue of what, if anything,
to do about minute, once-undetectable chemical traces that some evidence now
suggests might hold health hazards.
With much still unknown about phthalates, scientists and regulators at the
Environmental Protection Agency are moving cautiously. "All this work on
the effects of phthalates on the male reproductive system is just five years
old," says the EPA's leading phthalate researcher, L. Earl Gray. "There
appears to be clear disruption of the androgen pathway, but how? What are phthalates
To Rochelle Tyl, a toxicologist who works for corporations and trade groups
studying chemicals' effects on animals, the broader question is: "If we
know something bad is happening, or we think we do, do we wait for the data
or do we act now to protect people?" Based on her own studies of rodents,
Dr. Tyl says it is still unclear whether low levels of phthalates damage baby
Some countries have acted. In 2003, Japan banned certain types of phthalates
in food-handling equipment after traces turned up in school lunches and other
The European Union has recently banned some phthalates in cosmetics and toys.
In January, the European Parliament's public health committee called for banning
nearly all phthalates in household goods and medical devices. In July, the full
parliament asked the EU's regulatory body, European Commission, to review a
full range of products "made from plasticised material which may expose
people to risks, especially those used in medical devices."
With the controversy particularly hot in Europe, the European market for the
most common phthalate plasticizer, diethylhexyl phthalate, or DEHP, has fallen
50 percent since 2000, says BASF AG, the German chemical giant. In response,
BASF says it is ceasing production of DEHP in Europe this month. A spokesman
for the company says the cutback won't affect its phthalate production in the
The U.S. doesn't restrict phthalates, and has lobbied the EU hard in recent
years not to burden manufacturers with new regulations on chemicals. Still,
a few companies, under pressure from health groups, have agreed to abide by
European standards in their products sold in the U.S. Procter & Gamble
Co. said last year it would no longer use phthalates in nail polish. Last December,
Unilever, Revlon Inc. and L'Oreal SA's American unit promised to eliminate all
chemicals banned in European products from the same items in the U.S.
For medical bags and tubes, Baxter International Inc. pledged in 1999 to develop
alternatives to phthalate-containing PVC, as did Abbott Laboratories in 2003.
(Abbott has since spun off its hospital-products unit.) In a June study by Harvard
researchers of 54 newborns in intensive care, infants who'd had the most invasive
procedures had five times as much of the phthalate DEHP in their bodies -- as
measured in urine -- as did babies with fewer procedures.
Researchers aren't yet sure what this means. Another study by doctors at the
Children's National Medical Center in Washington, published last year, found
that 19 adolescents who'd had significant exposure to phthalates from medical
devices as newborns showed no signs of adverse effects through puberty.
Kaiser Permanente, the big health-maintenance organization, promised in 1999
to eliminate phthalates in hospital supplies. Demand from the HMO has helped
drive development of medical gloves that don't contain phthalates, as well as
non-PVC carpeting and a new line of phthalate-free plastic handrails, corner
guards and wall coverings.
In the early 1990s, the EPA set exposure guidelines for several types of phthalates,
based on studies that had been done decades earlier. Since then, much more has
been learned about them.
Consider dibutyl phthalate, which is used to keep nail polish from chipping
and to coat some pills. The EPA did a risk assessment of it 15 years ago, relying
on a rodent study performed in 1953. The now half-century-old study found a
"lowest adverse-effect level" -- 600 milligrams a day per kilogram
of body weight -- that killed half of the rodents within a week.
A 2004 study of the same chemical, published in the journal Toxicological Sciences,
found far subtler effects, at far lower exposures. It detected gene alteration
in fetuses of female rats that ingested as little as 0.1 milligram a day of
the phthalate for each kilogram of body weight. That dose is one six-thousandth
of the 1953 "lowest adverse-effect" level.
It's also an exposure level found in some U.S. women, says Paul Foster of the
National Institute of Environmental Health Sciences, a co-author of the gene
study. So "now we're talking about 'Josephina Q. Public' -- real women
in the general population," he says. "The comfort level is receding."
Still, because researchers don't know the function of the genes that were altered
in the rat study, EPA experts say it's too early to base regulatory decisions
on such gene changes. "We're a long way, in my opinion, from considering
changes in gene expression as 'adverse' for risk assessment," says the
environmental agency's Dr. Gray.
Exxon Mobil Corp. and BASF dominate the $7.3 billion phthalates market. An
Exxon Mobil spokeswoman says risk assessments by government agencies in Europe
and the U.S. confirm "the safety of phthalates in their current applications."
Phthalates are cheaper than most other chemicals that can soften plastics.
But a BASF press release says European manufacturers have been replacing phthalates
with plasticizers designed for "sensitive applications such as toys, medical
devices and food contact."
Makers of pills sometimes coat them with phthalates to make them easier to
swallow or control how they dissolve. A case study published last year in the
journal Environmental Health Perspectives said a man who took a drug for ulcerative
colitis, Asacol, for three months was exposed to several hundred times as much
dibutyl phthalate as the average American. The drug's maker, Procter &
Gamble, says it coats the pill with the phthalate so it will stay intact until
it reaches inflamed colon areas. P&G says a daily dose of the drug has
less than 1 percent of the 0.1 milligram of dibutyl phthalate per kilogram of
body weight that the EPA regards as a safe daily dose.
Attributing health effects to specific industrial chemicals is a dicey business.
Scientists often look for associations: statistical correlations that suggest,
but don't prove, a possible causal link.
With phthalates, they've found a few. For instance, a 2003 study divided 168
male patients at a fertility clinic into three groups based on levels of phthalate
metabolites in their urine. The study found that men in the highest third for
one of the phthalates were three to five times as likely as those in the lowest
third to have a low sperm count or low sperm activity. Men highest in a different
phthalate also had more abnormally shaped sperm, according to the study, which
was done by researchers at the Harvard School of Public Health and published
in the journal Epidemiology.
The scientists now are extending the research to 450 men. In their next paper,
they're also planning to discuss a separate Swedish study, of 245 army recruits,
that found no link between phthalate exposure and sperm quality.
The latest human study, on 96 baby boys in Denmark and Finland, found that
those fed breast milk containing higher levels of certain phthalates had less
testosterone during their crucial hormonal surge at three months of age than
baby boys exposed to lower levels.
Authors of the study, led by Katharina Main of the University of Copenhagen
and published Sept. 8 in Environmental Health Perspectives, said their findings
support the idea that the human testis is vulnerable to phthalate exposure during
development -- possibly even more vulnerable than rodents' genitalia. They added,
however, that "before any regulatory action is considered, further studies
on health effects of (phthalates) are urgently needed" aimed at "verifying
or refuting our findings."
A human study of 85 subjects published in June linked fetal exposure to phthalates
to structural differences in the genitalia of baby boys.
Researchers measured phthalate levels in pregnant women and later examined
their infant and toddler sons. For pregnant women who had the highest phthalate
exposure -- a level equivalent to the top 25 percent of such exposure in American
women -- baby sons had smaller genitalia, on average. And their sons were more
likely to have incompletely descended testicles.
Most striking was a difference in the length of the perineum, the space between
the genitalia and anus, which scientists call AGD, for anogenital distance.
In rodents, a shortened perineum in males is closely correlated with phthalate
exposure. A shortened AGD also is one of the most sensitive markers of demasculinization
in animal studies.
Males' perineums at birth are usually about twice as long as those of females,
in both humans and laboratory rodents. In this study, the baby boys of women
with the highest phthalate exposures were 10 times as likely to have a shortened
AGD, adjusted for baby weight, as the sons of women who had the lowest phthalate
The length difference was about one-fifth, according to the study, which was
led by epidemiologist Shanna Swan of the University of Rochester (N.Y.) School
of Medicine and Dentistry and published in Environmental Health Perspectives.
Among boys with shorter AGD, 21 percent also had incomplete testicular descent
and small scrotums, compared with 8 percent of the other boys.
Does it matter? The researchers intend to track as many of the boys as possible
into adulthood, to address a key question: Will they grow up with lower testosterone
levels, inferior sperm quality and higher rates of testicular tumors, as do
rats with phthalate syndrome?
When the boys are 3 to 5 years old, Dr. Swan plans to assess their play behavior
to see if exposure to phthalates appears associated with feminized neurological
development. She says such tests have shown that little girls with high levels
of androgens, or male hormones, gravitate toward "masculine" play.
But she says no one has studied whether boys' play is affected by fetal exposure
to chemicals that block androgens.
"In rodents, the changes result in permanent effects. Future studies will
be necessary to determine whether these boys are also permanently affected,"
Dr. Swan says.
She and others agree that a study of just 85 subjects needs to be enlarged
and repeated. She notes that although boys' genitalia were affected in subtle
ways, no substantial malformations or disease were detected.
Some endocrinologists call this the first study to link an industrial chemical
measured in pregnant women to altered reproductive systems in offspring. "It
is really noteworthy that shortened AGD was seen," says Niels Skakkebaek,
a reproductive-disorder expert at the University of Copenhagen, who wasn't an
author of the study. "If it is proven the environment changed the (physical
characteristics) of these babies in such an anti-androgenic manner, it is very
Ms. Stanley of the American Chemistry Council doubts that any study can "tease
out" the cause of a human health condition, given the wide variety of chemical
exposures in people's lives. She notes that some of the specific phthalates
associated with reproductive changes in the two human-baby studies haven't been
linked to such changes in rodents. So, she says, it's possible the changes in
anogenital distance and hormone levels may merely reflect normal variability.
Dr. Tyl, the chemical-industry toxicologist, says her own rat studies confirm
that AGD is very sensitive to phthalates. She says that in rats that had very
high phthalate exposures, a shortened AGD at birth was closely associated with
a number of serious reproductive disorders later in life. However, in rats exposed
to much lower doses of phthalates, a shortened AGD at birth did not always lead
to later troubles. Many of these rats grew up to breed normally, she says, despite
their slightly altered anatomy.
Dr. Tyl suggests that the same may be true of humans. Dr. Swan's study is "potentially
important," Dr. Tyl says, because it suggests that "at low levels
of exposure, humans are responding" to phthalates. But it remains quite
possible, Dr. Tyl theorizes, that the boys with shortened AGD will grow up normally.
"At what point do changes like this cross the line" to become dangerous,
she asks. "We don't know yet."