Tiny Toxins?

It was just the type of event that many in the nanotechnology community have feared – and warned against. In late March, six people went to the hospital with serious (but nonfatal) respiratory problems after using a German household cleaning product called Magic Nano. Though it was unclear at the time what had caused the illnesses – and even whether the aerosol cleaner contained any nanoparticles – the events reignited the debate over the safety of consumer products that use nanotechnology.

The number of products fitting that description has now topped 200, according to a survey published in March by the Project on Emerging Nanotechnologies in Washington, DC. Among them are additives that catalyze combustion in diesel fuel, polymers used in vehicles, high-strength materials for tennis rackets and golf clubs, treated stain-resistant fabrics, and cosmetics. These products incorporate everything from buckyballs – soccer ball-shaped carbon molecules named after Buckminster Fuller – to less exotic materials such as nanoparticles of zinc oxide. But they all have one thing in common: their “nano” components have not undergone thorough safety tests.

[Click here for a table of recent findings on toxicity associated with nano materials and devices.]

Nanoparticles, which are less than 100 nanometers in size, have long been familiar as by-products of combustion or constituents of air pollution; but increasingly, researchers are designing and synthesizing ultrasmall particles to take advantage of their novel properties. Most toxicologists agree that nanoparticles are neither uniformly dangerous nor uniformly safe, but that the chemical and physical properties that make them potentially valuable may also make their toxicities differ from those of the same materials in bulk form.

One of the reasons for concern about nanoparticles’ toxicity has to do with simple physics. For instance, as a particle shrinks, the ratio of its surface area to its mass rises. A material that’s seemingly inert in bulk thus has a larger surface area as a collection of nanoparticles, which can lead to greater reactivity. For certain applications, this is an advantage; but it can also mean greater toxicity. “The normal measure of toxicity is the mass of the toxin, but with nanomaterials, you need a whole different set of metrics,” says Vicki Colvin, a professor of chemistry at Rice University in Houston and a leading expert on nanomaterials.

Beyond the question of increased reactivity, the sheer tininess of nanoparticles is itself a cause for concern. Toxicologists have known for years that relatively small particles could create health problems when inhaled. Researchers have found evidence that the smaller particles are, the more easily they can get past the mucus membranes in the nose and bronchial tubes to lodge in the alveoli, the tiny sacs in the lungs where carbon dioxide in the blood is exchanged for oxygen. In the alveoli, the particles face the white-cell scavengers known as macrophages, which engulf them and clear them from the body. But at high doses, the particles overload the clearance mechanisms.

It is the potential growth, however, of technologies involving precisely engineered nanoparticles, such as buckyballs and their near cousins, carbon nanotubes, and the use of these new materials in consumer products that has made the question of toxicity particularly urgent.

In addition to questions about how easily nanoparticles can penetrate the body, there is also debate over where they could end up once inside. Günter Oberdörster, a toxicologist at the University of Rochester, found that various kinds of carbon nanoparticles, averaging 30 to 35 nanometers in diameter, could enter the olfactory nerve in rodents and climb all the way up to the brain. “There is a possibility that because of their small size, nanoparticles can reach sites in the body that large particles cannot, cross barriers, and react,” says Oberdörster.

In 2004, Oberdörster’s daughter, Eva Oberdörster, a toxicology researcher at Duke University, put largemouth bass into water containing buckyballs at the concentration of one part per million. After two days, the lipids in the brains of the fish showed 17 times as much oxidative damage as those of unexposed fish.

Carbon nanotubes, which are basically cylindrical versions of the spherical buckyballs, are one of the stars of nanotech, with potential uses in everything from solar cells to computer chips. But in 2003, researchers at NASA’s Johnson Space Center in Houston, headed by Chiu-Wing Lam, showed that in the lungs of mice, carbon nanotubes caused lesions that got progressively worse over time. Under the conditions of the experiment, the researchers concluded, carbon nanotubes were “much more toxic than carbon black [that is, soot] and can be more toxic than quartz, which is considered a serious occupational health hazard.”

Another extremely promising nanoparticle is the fluorescent “quantum dot,” now being explored for use in bioimaging. Researchers envision applications in which they tag the glowing nanodots with antibodies, inject them into subjects, and watch as they selectively highlight certain tissues or, say, tumors. Quantum dots are typically made of cadmium selenide, which can be toxic as a bulk material, so researchers encase them in a protective coating. But it is not yet known whether the dots will linger in the body, or whether the coating will degrade, releasing its cargo.

Sensible regulation of nanoparticles will require new methods for assessing toxicity, which take into account the qualitative differences between nanoparticles and other regulated chemicals. Preferably, those methods will be generally applicable to a wide spectrum of materials.

Today’s assays are not adequate for the purpose, says Oberdörster. “We have to formalize a tiered approach,” he says, “beginning with noncellular studies to determine the reactivity of particles, then moving on to in vitro cellular studies, and finally in vivo studies in animals. We have to establish that some particles are benign and others are reactive, then benchmark new particles against them.”

Separately testing every newly developed type of nanoparticle would be a Herculean task, so Rice’s Colvin wants to develop a model that indicates whether a particular nanoparticle deserves special screening. “My dream is that there would be a predictive algorithm that would say, for a certain size and surface coating, this particular type of material is one you’d want to stay away from,” she says. “We should be able to do it, with the advance we have made in computing power, but we have to ask the right questions. For instance, is it acute cytotoxicity, or is it something else?”

Amidst all the uncertainty about evaluating nanoparticles’ toxicity, regulatory agencies are in something of a quandary. In the United States, the Food and Drug Administration will assess medical products that incorporate nanoparticles, such as the quantum dots now being tested in animals; the Occupational Safety and Health Administration is responsible for the workplace environment in the factories that make the products involving nanoparticles; and the Environmental Protection Agency looks at products or chemicals that broadly permeate the environment, like additives to diesel fuel. In principle, these federal agencies have sweeping power over nanomaterials, but at the moment, their traditional focus, their limited resources, and the sheer lack of test tube and clinical data make effective oversight next to impossible.

For example, the National Institute for Occupational Safety and Health, the part of the Centers for Disease Control and Prevention in Atlanta responsible for studying and tracking workplace safety, acknowledges that “minimal information” is available on the health risks of making nanomaterials. The agency also points out that there are no reliable figures on the number of workers exposed to engineered nanomaterials.

The EPA seems further along. In its draft “Nanotechnology White Paper,” issued in December, it proposed interagency negotiations to hammer out standards and pool resources. It acknowledged that at present, some nanoparticles that should be under its review are not, because they are not included in the inventory of chemicals controlled under the Toxic Substances Control Act.

The EPA must defend the safety not only of human beings but of the natural environment – plants and ecological systems that may be exposed to a regulated material. There is scant data on the effects of nanomaterials in the environment, but some of it is troubling. One study, for example, showed that alumina nanoparticles, which are already commonly used, inhibit root growth in some plants.

In a report written for the Project on Emerging Technologies, J. Clarence Davies, assistant administrator for policy, planning, and evaluation at the EPA from 1989 to 1991, advocates passing a new law assigning responsibility for nanomaterial regulation to a single interagency regulatory authority. Davies would also require manufacturers to prove their nanotech products safe until enough evidence had been gained to warrant exemptions.

But some executives in the nanotech industry cringe at the prospect of such regulations. Alan Gotcher, head of Altair Nanotechnologies, a manufacturer in Reno, NV, that makes various types of nanoparticles, testified before the U.S. Senate in February and cited the Davies report. “To fall into ‘a one-size-fits-all’ approach to nanotechnology,” he said, “is irresponsible and counterproductive.” Gotcher would prefer a government-funded effort to amass the necessary data and build the necessary models before setting any standards.

It is doubtful, however, that the nanotech community will stop developing new products, or that the public will stop buying them, while awaiting a new regulatory framework that could take years and millions of dollars to finalize. While few agree on how to efficiently determine the toxicity of nanoparticles, or how to regulate them, nearly everyone agrees on the urgency of quickly tackling both questions.

The use of nanoparticles in consumer products like cosmetics and cleaners represents only a tiny sliver of nanotech’s potential, but any unresolved safety concerns could cast a huge shadow. “If I was someone producing these materials, I would be afraid that one health problem, anywhere, would hurt the entire industry,” says Peter Hoet, a toxicologist at the Catholic University of Leuven, in Belgium.

The large consumer corporations DuPont and Procter and Gamble participated in a study on nanoparticles’ toxicity. But the nanotech community needs to put pressure on manufacturers using the “nano” label for marketing purposes to stand up and take responsibility for their products. That means contributing resources and money to toxicity studies and freely disclosing which nanotechnologies they are relying on.

Philip E. Ross writes on science and technology from New York City.

Home page illustration by Jason Holley.