EPA should test demasculinizing pollutants collectively, NRC says

On December 18, a National Research Council panel told the Environmental Protection Agency that sufficient data exist to begin assessing the potential health risks posed by phthalates, among the most ubiquitous pollutants on the planet. At the same time, the NRC panel strongly recommended that the agency adopt a “paradigm shift” in the way it assesses the chemicals’ toxicity to humans.

Instead of evaluating each phthalate compound individually, EPA should begin assessing risks from likely combos of these and related chemicals — even if each chemical works differently, according to the panel’s new report.

Phthalates are a widely used family of plasticizers and solvents. Owing to the chemicals’ presence in plastics, cosmetics, personal care products and even medicines, residues of these chemicals show up in everyone throughout the developed world.

For more than a decade, studies in rodents have been demonstrating that exposures to phthalates early in life can perturb — in some cases derail — development of an animal’s reproductive organs (SN: 9/2/00, p. 152). Males are most sensitive, largely because these chemicals act as anti-androgens. That is, the chemicals lower concentrations of testosterone, the primary male sex hormone. Especially concerning: In females, phthalates can cross the placenta and pollute the womb.

The NRC panel advocated that EPA assess cumulative risks from all phthalates and other anti-androgenic compounds together — even if the way each pollutant depresses testosterone action or availability results from differing modes of action.

Whether these pollutants pose serious risks to people remains an open question, acknowledged several authors of the NRC report, who took part in a teleconference for the report’s release.

EPA didn’t ask NRC to assess phthalates’ toxicity to humans, notes Deborah Cory-Slechta of the University of Rochester School of Medicine and Dentistry in New York. Instead, EPA asked her panel to evaluate whether sufficient data exist to conduct a human risk assessment. And if so, how should the risks be evaluated: on the basis of single compounds considered separately, as a group evaluated together, or as a group assessed along with additional anti-androgenic agents.

Cory-Slechta says her panel found that there are plenty of data for EPA “to go ahead and do it [a human risk assessment].” But the panel also recommended that when EPA does such an assessment, it should take a sharply different tack from its normal approach.

To Shanna Swan, a phthalate researcher at the University of Rochester, the recommended change in how to calculate the risk of these chemicals “is a big deal. Cumulative risk assessment is the way it must be done,” she says, “given the dose additivity of these chemicals and the multiplicity of our exposures.”

Most people regularly encounter many phthalates, and as a class these compounds tend to have similar impacts. So, even if each of five phthalates had no apparent effects at a particular dose when delivered individually, coincident exposure to the mix might easily prove to compound the toxicity, the new report explained.

Indeed, published data show that “phthalates can work together at quite low doses,” noted NRC panel member Andreas Kortenkamp of the University of London School of Pharmacy in England. “So if combination effects were not taken into consideration at this level, we would underestimate possible risks.” In fact, he said, his committee’s new paradigm for considering phthalate toxicity cumulatively must inevitably result in findings of higher risks than would have been calculated by assessing each chemical in isolation.

In the new report, NRC concluded that a lifelong testosterone shortfall triggered by phthalate exposures can cause “the variety of effects observed” in animals — including infertility, reduced sperm production, undescended testes, penile birth defects and other reproductive-tract malformations — “if it occurs at times that are critical for male reproductive development.” The most sensitive exposure period: time in the womb.

Indeed, concentrations of phthalates measured in amniotic fluid in the human womb can be “in the range of levels in rat amniotic fluid that gives rise to adverse effects in the offspring,” Kortenkamp said.

However, links to human effects have been quite limited, observes panel member Paul Foster of the National Institute of Environmental Health Sciences in Research Triangle Park, N.C. One exception: a study of infant boys linking phthalate exposure in the womb to a feminization of the anogenital distance — the span separating the gonads and anus (SN: 6/4/05, p. 355).

In rodents, this distance is demonstrably longer in males. In fact, researchers depend on this sex-linked distance to visually determine the gender of young rodents.

Follow-up studies are needed with more subjects to test the validity of those preliminary data, Foster says. That said, this phthalates toxicologist points out that the general processes by which these chemicals interfere with sexual differentiation “are common to all mammals. And so, having seen them in rats, one would not expect them not to occur in humans — providing, of course, the exposure was high enough.”