New(?) Concerns about Phthalates

Ingredients of common plastics, may harm 'boys' as they develop.

S/N Vol 158 #10

Phthalates. Difficult to spell and harder to sound out, this class of compounds would be forgettable if name didn't keep popping up in debates over the safety of intravenous-blood bags, food packaging, and children's toys.

Phthalates have become ubiquitous in modern society. Some of these oily substances find use as solvents, but most serve as softeners that make rigid materials turn flexible. Worldwide, manufacturers produce an estimated billion pounds of phthalates annually.

Despite a half century of apparently safe use, several environmental and health groups and the U.S. Consumer Product Safety Commission in late 1998 called for the manufacturers of toys, baby pacifiers, and medical supplies to remove the most toxic of these chemicals from their products. At that time, scientists had linked cancer in adults to heavy exposure to some phthalates, animal studies had indicated that phthalates never cause organ damage, and chemists had demonstrated that phthalates could leak from plastics during use.

At least a few phthalates also have the potential to disrupt boys' reproductive development. Or so a federally appointed "panel of experts" has just concluded after 15 months of deliberation and a review of some 1,000 studies.

The new phthalate review was commissioned by the National Toxicology Program's Center for the Evaluation of Risks to Human Reproduction (CERHR). It was the first project of this 2-year-old center, which is part of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C..

The review focused exclusively on the compounds' potential for causing birth defects or reproductive abnormalities. Over the past 3 years, animal experiments have indicated that low exposures can grossly alter the organs that in adults produce and deliver sperm.

The evaluators noted, however, that low phthalate concentrations show damage to animals only when the exposure takes place during some precise window of vulnerability. This period in test animals approximately corresponds to the end of a woman's first trimester of pregnancy, a time when many women don't yet realize they're carrying a child.

Several health and environmental advocacy groups have trumpeted the panel's assessments, renewing their call for a phaseout of targeted products containing certain phthalates. The CERHR panel itself didn't go that far. In fact, the group argued that panic is unwarranted.

Except for data on the most widely used phthalate, di-2-ethylhexyl phthalate (DEHP), much of the human-exposure and reproductive-toxicity data now available are rather preliminary or sketchy, the panel observed. Moreover, could identify only a few, relatively small populations that might encounter significant exposures during periods when vulnerable tissues are developing. And, in at least some cases, it concluded, any risks from phthalate exposure might be outweighed by the benefits such products offer.

Still, notes panel chairman Robert J. Kavlock, who directs reproductive toxicology at the Environmental Protection Agency in Research Triangle Park, "I don't think we gave a clean bill of health to any [phthalates]. We didn't say there was no risk."

Though his panel slogged through nearly 600 studies on DEHP and almost as many for another six phthalates, it didn't find answers to many pressing questions about developmental toxicity. Lingering doubts about the phthalate's toxicity, after so many studies, "seems to speak to the fact that somehow the right studies weren't being conducted," observes CERHR director Michael D. Shelby.

One reason, Kavlock notes, is that researchers had designed most phthalate studies to evaluate risk of cancer or infertility in adults exposed to the chemicals in the workplace.

"Most of those data were also 20 years old or more," adds panelist Paul M.D. Foster, a reproductive toxicologist at the Chemical Industry Institute of Toxicology (CIIT) in Research Triangle Park. Only about 5 years ago did scientists first suspect that phthalates might affect babies in ways that could eventually impair their reproduction (SN: 7/15/95, p. 47), and that suspicion was confirmed even more recently.

In its report, due out in October, the panel will recommend research to fill the data gaps it found. Independently within the next month, the results of several long-awaited studies are expected to fill in a few major gaps in the phthalate story, Kavlock notes.

One of those studies should offer the best measurement yet of phthalate exposures in the general population. Analytical chemist John Brock started contemplating that issue 7 years ago, as a result of tests he conducted shortly after joining the Centers for Disease Control and Prevention in Atlanta. While using gas chromatography to scout for pesticides and related pollutants in human blood, he found a handful of seemingly unbelievable readings.

A gas chromatograph portrays chemicals within a sample as a series of peaks rising from a horizontal line. The height of each peak denotes a constituent's quantity. However, the peaks of two very different compounds occasionally fall in the same position.

Brock suspected this must explain a few of the loftier peaks from the blood samples. A spike at the address ordinarily marking lindane, a toxic pesticide, for instance, was hundreds of times higher than the value typically found in people.

Turning to mass spectrometry, which determines the size of the molecules contributing to each peak, he confirmed that the spike at lindane's address actually traced to di-ethyl phthalate. Several other chemical Himalayas on Brock's printout also turned out to be phthalates.

When he showed his data to a colleague, he learned that phthalates had been showing up in environmental samples for 20 years. Researchers had assumed, says Brock, that the chemicals were contaminants entering their samples after they had been collected--probably coming from labware, flooring, paint, or labworkers' cosmetics.

However, Brock wondered, what if that assumption was wrong? As he recalled last June at a workshop in Bar Harbor, Maine, Brock worried that the lofty peaks he had detected 7 years ago truly reflected phthalate concentrations "in most people at the parts-per-million level." That would be far higher than ever anticipated.

For the past 5 years, Brock has been developing a marker of phthalates in the body that can't be confused with contamination. The test homes in on phthalate fragments created by enzymes and shed in urine. Brock's upcoming report will reveal the test's measurements of phthalate in U.S. adults.

Talk at the CERHR panel's final meeting on phthalates in mid-July hinted that Brock has found phthalate exposures in some of the population greatly exceeding earlier estimates.

L. Earl Gray Jr., a phthalate toxicologist with EPA in Research Triangle Park, has also heard the reports. He notes that the exposures needed to induce male reproductive-system birth defects in his own animal studies (SN: 4/3/99, p. 213) "probably won't turn out to be any higher than those in some of the people Brock is talking about."

While Brock will neither confirm nor deny speculation about his findings on human urine, Gray willingly discusses his new research on rats. In a report scheduled for publication Toxicology Sciences, Gray finds that the demasculinizing toxicity of phthalates depends on their molecular shape.

The EPA researcher gave pregnant rats one of six phthalates, in daily doses of 750 milligrams per kilogram of body weight, throughout the period when their pups' sexual organs were developing. DEHP triggered defects in male reproductive tissue. So did BBP (benzyl butyl phthalate), a compound that goes into floor tiles, adhesives, and artificial leather. DINP (di-isononyl phthalate), used in polyvinyl-chloride products from garden hoses to toys, proved less potent, but relatively large quantities could elicit such birth defects, Gray notes.

New EPA data from other researchers find that DEHP, BBP, and DINP can all lower fetal concentrations of testosterone, the primary male sex hormone, during this developmental period. Gray's data link such a short-circuiting of the male pups' testosterone production to structural similarities in the toxicants.

Phthalates are ring-shaped molecules adorned with two side chains, known as esters. Those phthalates that disrupt early testosterone production tend to carry relatively short esters that dangle off the same side of the ring, he finds. Move one of the esters to the opposite side of the ring, he notes, and the compound loses its developmental toxicity.

Last year, Foster's team reported that di(n-butyl) phthalate, or DBP, can also ratchet down the activity of enzymes vital to making testosterone in fetal testes (SN: 4/3/99, p. 213). Affected animals are born with a variety of malformations. Manufacturers use DBP in plastics, adhesives, cosmetics, dyes, and food wraps (SN: 7/15/95, p. 47).

These findings, Gray maintains, argue that it would be a mistake to blame all phthalates for the demasculinizing toxicity that may trace to just a few. However, those that inhibit testosterone probably should be considered collectively, he says, since their effects "would almost certainly be additive."

Both the CIIT and EPA groups are now trying to discover which genes fail to turn on when a young male's testosterone production remains low. The targets for the missing componets also remain unknown. Gray says that he hopes they won't turn out to be Sertoli cells. In adults, these specialized residents of the testes nurture a developing sperm's every need (SN: 1/22/94, p. 57). If phthalates indirectly harm immature Sertoli cells, he worries, "it's possible the testes could remain susceptible 'til puberty."

In addition to considering DEHP, BBP, DINP, and DBP, the 15-member panel reviewed data on di-isodecyl, di-n-hexyl, and di-n-octyl. The panel, primarily made up of federal and university scientists, asked three questions for each compound: Do the available animal data indicate developmental or reproductive toxicity? Which human populations would be most vulnerable? and, would such populations likely encounter toxic concentrations?

After much deliberation, the panel concluded that five of the seven compounds appear to pose "low, minimal, or negligible concern" to the general population, including pregnant women and toddlers who tend to mouth plastic objects. However, the panel found "too few data ... to reach any conclusions" about di-n-hexyl phthalate. This compound goes into auto parts, tool handles, flooring, flea collars, and dishwasher baskets.

In prevalence and toxicity, DEHP left the panel with the greatest concerns. A loosely bound ingredient in the plastics used for toys, food packaging, and household products, DEHP taints the air, water, and many foods.

Normal, ambient exposure to this phthalate might be sufficient to threaten male reproductive organs developing in a healthy fetus, infant, or toddler, the panel concluded. It expressed "serious concern" that critically ill babies might be harmed. U.S. hospitals today dispense blood and liquid foods from DEHP-softened vinyl bags and tubing. What's more, some respiratory-care supplies are made from or packaged in DEHP-softened plastics.

Ordinarily, regulatory agencies impose a safety margin when setting guidelines for exposures to toxic substances. For instance, if adverse effects are found at a given concentration, safety rules usually limit exposures to one-thousandth that concentration or less. However, the panel said that exposure estimates indicate some hospitalized children might encounter heavy, prolonged DEHP exposure--equivalent to the amounts that induced male reproductive impairments in animals. As such, the panel concluded, "there may be no margin of safety."

Notwithstanding, the scientists acknowledged that the benefits of medical care employing DEHP-laced plastics might still outweigh such risks.

After a 60-day public-comment period on the panel's findings, the National Institute of Environmental Health Sciences will sum up the assessments and pass them along to various agencies. These will include the Food and Drug Administration, which is completing its own evaluation of DEHP's toxicity. Last year, citing concern over developmental risks, a citizens' group--lthe Minneapolis-based Health Care Without Harm--petitioned the agency for mandatory labeling of blood-storage bags and other products containing DEHP.

California's Office of Environmental Health Hazard Assessment--better known as theProposition 65 office--has also been following the expert panel's review carefully. It too plans to decide soon whether DEHP's developmental and reproductive risks warrant mandatory product-warning labels. Such labeling might spur U.S. industries to seek substitutes more aggressively, especially for consumer and health-care products, observes Colleen Heck, chief counsel for the state's Proposition 65 office in Sacramento.

Such changes could have an impact nationally. California accounts for up to 20 percent of U.S. sales for many products, Heck observes. A manufacturer who wants to do business in California, therefore, tends to deal with affected products--by either slapping warning labels on each package or changing the product as if all of it would be sold in the state.

Indeed, she says, "we have been told, anecdotally, of millions of dollars being spent to reformulate products so that manufacturers can avoid labeling them as containing something that causes cancer or birth defects." Then again, she adds, that's what the Proposition 65 office was designed to do: offer information so that consumers have the option of "driving changes in the marketplace."

However, getting rid of DEHP in medical goods would initially require more than switching to some other plastic. At an FDA workshop in October 1999, participants noted that DEHP has offered some initially unanticipated dividends. For reasons that aren't completely understood, they noted, this softener also subtly changes any blood stored in plastics containing it, extending the blood's shelf life and improving its functional quality.

So "we cannot immediately remove DEHP" and replace it with just any plasticizer, argued James AuBuchon, director of blood bank and transfusion services at Dartmouth-Hitchcock Medical Center, in Lebanon, N.H.

Indeed, a few firms have already, at great cost and after lengthy testing, developed alternative plastics for blood storage--only to find no buyers.

Girls may face risks from phthalates.

Janet Raloff

Physically precocious young girls often must endure stares and nasty catcalls. The problem of early development is particularly prevalent in Puerto Rico, and researchers there have found a possible culprit.

For more than 2 decades, their island has hosted an inexplicable epidemic of premature breast development, or thelarche. The incidence there--at least 7 or 8 per 1,000 girls--is the highest known. Most of the affected girls begin developing breasts between the ages of 6 and 24 months, notes Carlos J. Bourdony, a pediatric endocrinologist at San Juan City Hospital.

In the September Environmental Health Perspectives, he and his colleagues at the University of Puerto Rico, San Juan report data linking this condition with phthalates, a family of ubiquitous pollutants. The chemicals are used in the manufacture of many products, among them, plastics, lubricants, and solvents.

These are the same compounds that a panel commissioned by the National Toxicology Program (NTP) recently concluded may harm reproductive development in boys (SN: 9/2/00, p. 152).

The San Juan researchers had thought that the thelarche might trace to pesticides that mimic estrogen, a hormone that spurs breast development. However, when they compared the blood of 41 girls with premature thelarche with that of 35 who are developing normally, "we did not find pesticides or their metabolites at higher levels," notes University of Puerto Rico chemist Osvaldo Rosario.

"What we did see more of in girls with premature breast development," he says, "were phthalates," chemicals that can mimic or alter activity of sex hormones in animals. Within the premature thelarche group, 24 girls (68 percent) had detectable phthalates in their blood, compared with just 6 (17 percent) of the girls developing normally.

The most dramatic difference showed up in the blood concentrations of di-2-ethylhexyl phthalate (DEHP), the most widely used phthalate. In the five normal girls whose blood contained DEHP, its concentration averaged 70 parts per billion; among the girls with premature breast development and detectable DEHP, the concentration averaged 450 ppb.

Such data fall far short of proving that phthalates play a role in thelarche, observes Shanna H. Swan of the University of Missouri in Columbia. Still, she says, the study "is definitely important" and offers the strongest potential explanation yet for Puerto Rico's early-thelarche rate.

Marcia E. Herman-Giddens of the University of North Carolina School of Public Health in Chapel Hill suggests that the phthalate connection may also help explain a disturbing trend that she and her colleagues reported 3 years ago. They found that the age at which U.S. girls enter puberty has been falling (SN: 5/3/97, p. 272). Herman-Giddens suspects that several factors--such as genetics and obesity--conspire with pollutants to hasten puberty.

If phthalates play a role, diet may be a major source. A recent study led by Jens H. Petersen of the Institute of Food Research and Nutrition in Seborg, Denmark, found phthalates in baby food and formulas. Fetal exposure to phthalates is also possible.

In fact, women of childbearing age had significantly higher phthalate exposures than any other group in a recent survey, according to John W. Brock of the Centers for Disease Control and Prevention in Atlanta. He recently measured phthalate breakdown products in the urine of 289 U.S. men and women. Surprisingly, among the women, the biggest contributor--di-ethyl phthalate (DEP)--is a solvent in colognes. Commercial production of DEP is far less than that of the phthalate plasticizers. Brock's findings will appear in the October Environmental Health Perspectives.

The good news, says toxicologist Paul M.D. Foster of the Chemical Industry Institute of Technology in Research Triangle Park, N.C., is that extensive tests show that DEP "doesn't have reproductive effects." Unfortunately, his data on developing male rodents show considerable reproductive toxicity for another pollutant that Brock detected in the young women: di-butyl phthalate (DBP). This phthalate appears in fingernail polish, dyes, and plastics such as those in some food wraps.

When the NTP panel reviewed phthalates' reproductive effects, Foster notes, it assumed that women would be exposed to less than one-tenth the concentration of DBP that Brock's team measured in the urine of his female participants. In light of the new data, Foster says, "I hope NTP reevaluates [DBP's] risk."

2007 Califronia Bans Phthalates in Plastic Toys

In October, governor Arnold Schwarzenegger signed into law a bill prohibiting phthalates in products intended for young children. "These chemicals threaten the health and safety of our children at critical stages of their developement," Schwarzenegger said. Proponents of the law are now pushing for similar action in states across the country and in congress.

Phthalate exposure from drugs?

A regimen of prescription pills may explain the highest blood concentration of a phthalate ever observed, medical researchers say. Phthalates are used as solvents, in plastics formulations, and for other purposes.

Last year, Russ Hauser of the Harvard School of Public Health in Boston and his colleagues found that men with high exposures to certain phthalates are likely to have sperm abnormalities (SN: 5/31/03, p. 339: http://www.sciencenews.org/articles/20030531/fob1.asp).

Phthalates are common in people's urine, but how these chemicals get into the body has remained unclear. Contact with phthalate-containing plastics and cosmetics is one likely path of exposure. Oral medications, which are sometimes coated with phthalates to control when the pills dissolve, could be another. [S/N Week of April 3, 2004; Vol. 165, No. 14 , p. 221

Can phthalates subtly alter boys?

From New Orleans, at the e.hormone 2004 conference

To identify a young rodent's gender without doing an elaborate test, biologists measure the distance from the animal's anus to its genital opening. This anogenital distance is slightly, but reliably, longer in males than in females-unless those males were exposed in the womb to pollutants, such as phthalates, that can alter fetal sex-hormone production. When that happens, a male's anogenital distance can become more similar to that of a female. Preliminary data suggest a similar trend in boys whose mothers were exposed during pregnancy to elevated amounts of some phthalates.

Phthalates, chemicals used in making many cosmetics, plastics, and other products, have become ubiquitous pollutants.

Epidemiologist Shanna H. Swan of the University of Missouri in Columbia and her colleagues collected urine samples from pregnant women in four U.S. cities. Tests for phthalate-breakdown products indicated that all the women had been exposed to phthalates, Swan reported. However, the amount of exposure varied from city to city. For instance, residues from certain phthalates were 40 to 90 percent higher in the women from Columbia than in those from Minneapolis. [Excerpt from S/N Week of Nov. 13, 2004; Vol. 166, No. 20 , p. 318]

How polluted we are

S/N Week of April 7, 2001; Vol. 159, No. 14 , p. 221

Though toxic compounds pervade the air we breathe, the water we drink, and the foods we eat, they only pose risks if they enter our bodies in biologically active quantities. To evaluate people's uptake of 27 would-be poisons, federal scientists surveyed blood and urine from 3,800 randomly chosen children and adults. The findings, released March 21, show that most people carry traces of the toxic pollutants.

Researchers with the Centers for Disease Control and Prevention (CDC) in Atlanta analyzed samples collected in 1999 as part of its ongoing National Health and Nutrition Examination Survey (NHANES).

Earlier, federal scientists surveyed a cross-section of the U.S. population for lead, cadmium, and cotinine (a marker of nicotine). This time, the CDC also assayed 24 other metals, pesticides, and phthalates, ubiquitous compounds that are used as solvents and as softeners in plastics.

The new data show that over just one decade, the average blood concentration of cotinine fell a whopping 75 percent-to 0.05 nanograms per milliliter. Residues of lead in blood fell about 26 percent, with concentrations in children now averaging 2 micrograms per deciliter. Though no amount of lead in blood is deemed safe, most concern focuses on values above 10 micrograms per deciliter.

Among the most eagerly awaited findings from this study were values for phthalates. These chemicals have gained notoriety for being able to impair male sexual development in animals (SN: 9/2/00, p. 152) and possibly to foster breast development in preschool girls (SN: 9/9/00, p. 165).

Phthalate urine residues were highest for diethyl phthalate (DEP), a solvent used in cosmetics. Average concentrations hovered about 171 micrograms per liter in urine, with 10 percent of people carrying concentrations 7 times that. Dibutyl phthalate (DBP), a solvent used in dyes, fingernail polish, and some plastics, was the second most prevalent of these compounds. Its residues averaged 28 micrograms per liter. Ironically, commercial production of both the phthalates pales next to that of diethyl hexyl phthalate and other such plasticizers. CDC scientists found that the diethyl hexyl residues average just 3.3 micrograms per liter.

The agency says its new data have prompted it to launch studies of why people are picking up such comparatively high concentrations of DEP and DBP.

Infants pick up toxic chemicals in intensive care

S/N Week of Aug. 13, 2005; Vol. 168, No. 7 , p. 109

Neonatal intensive care units routinely save the lives of extremely premature and critically ill newborns. Many of these successes are made possible by tubing and other equipment rendered flexible with a plasticizer known as diethylhexyl phthalate (DEHP). A new study finds that this equipment releases DEHP into the babies, though the impact on such children is still uncertain.

Everyone carries at least traces of phthalates, which are ubiquitous pollutants (SN: 2/22/03, p. 120: Available to subscribers at http://www.sciencenews.org/articles/20030222/bob9.asp). However, DEHP in neonates is a special concern because "it is a reproductive and developmental toxicant in laboratory animals," says study author Russ Hauser of the Harvard School of Public Health in Boston.

Hauser and his colleagues collected urine from 54 infants in intensive care. Tests at the Centers for Disease Control and Prevention in Atlanta turned up a metabolic breakdown product of DEHP in nearly every sample, the team reports in the September Environmental Health Perspectives.

The researchers had logged all DEHP-containing equipment to which each child was exposed, including breathing and feeding tubes, lines carrying blood to an oxygenation machine, and catheters. Grouped into three levels of the children's exposures to plastics during intensive care, urine concentrations of the DEHP marker correlated with the extent of exposure.

Urine from the highest-exposure group contained five times the concentration of the marker as did urine from the least-exposed babies, and infants intermediately exposed to DEHP had medium concentrations of the chemical marker. The highest marker concentrations in the study were up to 20 times as high as those reported in studies in healthy toddlers. To date, no adverse impact has been reported among children with known exposures to DEHP.

Many plastic hospital products that are low in or devoid of phthalates are available, Hauser notes, adding that they might be particularly appropriate for infants in intensive care, who are "being exposed at a sensitive window" of development.