New Concerns about Phthalates

Phthalates. Difficult to spell and harder to sound out, this class of compounds would be forgettable if the 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 can 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, it 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.”

Lingering doubts

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.

Best measurement yet

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: https://www.sciencenews.org/sn_arc99/4_3_99/fob3.htm) “probably won’t turn out to be any higher than those in some of the people Brock is talking about.”

Toxicity depends on shape

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: https://www.sciencenews.org/sn_arc99/4_3_99/fob3.htm). 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: https://www.sciencenews.org/sn_edpik/ls_8.htm). If phthalates indirectly harm immature Sertoli cells, he worries, “it’s possible the testes could remain susceptible ’til puberty.”

Three questions

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.

Summing up

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 the Proposition 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.