Wall Street Journal (pg. A1)
October 4, 2005


Male Reproductive Development Is Issue With Phthalates, Used in Host
of Products; Europe, Japan Restrict Them

By Peter Waldman.

[Third in a Series]

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% 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

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

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 doing?"

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 boys.

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 foods.

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% 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 U.S.

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% 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% 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

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 exposures.

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%
also had incomplete testicular descent and small scrotums, compared
with 8% 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

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 serious."

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


Phthalates in Beauty Products

Though seldom listed on labels, phthalates are common in personal-care
products,one of many ways the chemicals enter the bloodstream.

Diethyl Phthalate, solvent and fixative in fragrances. Has been linked
to DNA change in human sperm.*

Dibutyl Phthalate, plasticizer and fixative. Has been linked to
physical changes in male human and rodent newborns.**

Prevalance in products tested Concentrations (parts per million)
Hairspray 63% of products
tested contained... 81 to 204 16 to 54
Deodorant 67% 38 to 2,933 104
Nail polish 67% (Diethyl) 75% (Dibutyl) 1,136 742 to 59,815
Hair mousse 80% 31 to 128 31 to 43
Fragrances 100% (Diethyl) 0% (Dibutyl) 5,486 to 38,663 Not Detected

*Duty, SM, NP Singh et al., Environmental Health Perspectives, July

**Swan, SH, KM Main et al., Environmental Health Perspectives, June

Source: U.S. Food and Drug Administration