Photo by Sam Kaplan for Fortune

Nanoparticles touch nearly every Fortune 500 company and aspect of our lives. They’re in everything from snack foods to clothing to sunscreen. There’s just one problem: We know very little about what happens when they pile up in the environment—or inside us.

ABOVE — Left: The concentration of nano titanium dioxide, a common whitener, is greater than 10% in certain powdered doughnuts, according to a 2012 study. The nanomaterial is widely used in candies, sweets, and chewing gum. Right: Eight out of 10 of the leading beauty brands have been found to contain nanoparticles that act as “penetration enhancers.” Photo by Sam Kaplan for Fortune

A few years ago

Arturo Keller began spending an awful lot of time working with pigskin—spreading things on it, lighting it up, heating it, looking at it under a microscope. He had no broader porcine predilection. No reason to study the whole hog. But the skin of pigs held a particular appeal for him because of its similarity to human skin. (And for obvious reasons he can’t work with that.) Assisted by his students, Keller, a chemist and environmental scientist at the University of California at Santa Barbara, spread a solution containing a material common in cosmetics, sunscreens, and lotions on the pigskins. The samples were then exposed to ultraviolet rays—some placed under a special lamp designed to replicate sunlight and others next to a window to soak up the real thing. Keller and his team were curious to see how the light would affect the solution’s main ingredient: nano titanium dioxide.

Keller felt it was especially important to understand how the material would behave on skin. Titanium dioxide is chemically inert and has for decades entered humans, often during surgery and frequently as part of a joint replacement. But shrunk way, way down to nano size, titanium dioxide acts quite differently than it does under normal circumstances. In general, things get weird on the nanoscale, which is often not much more than a few atoms stuck together. If the width of a human hair were the size of the Empire State Building, a nanoparticle would be an ant. At that scant size, substances take on new properties.

Nano-size titanium dioxide, in particular, can sneak into parts of the body that most particles cannot—such as bone marrow, ovaries, lymph nodes, and nerves. It can also cross the blood-brain barrier or enter cells and destroy genetic material. The particles have been found to accumulate in the small intestine, particularly in areas used by our immune system. In 2010 a molecular biologist at UCLA’s School of Public Health began lacing drinking water with nano titanium dioxide, gave it to mice, and quickly found it was wreaking havoc on the animals’ chromosomes and DNA, which can lead to increased rates of cancer, as well as heart and neurological diseases. The International Agency for Research on Cancer (part of the World Health Organization) has linked nano titanium dioxide in powder form to cancers, especially when inhaled.

The substance is commonly added to products we use everyday. The Environmental Working Group, a research organization based in Washington, D.C., estimates that nano titanium dioxide is in about 10,000 over-the-counter products, even food. The particle reflects light well, and studies in 2013 found it was a common whitener in foods, showing up in powdered doughnuts made by Dunkin’ Brands and Donettes made by Hostess. (Hostess did not respond to a request for comment. A Dunkin’ spokesperson says its ingredient doesn’t meet the FDA’s definition of a nanoparticle, but adds, “We are in the process of rolling out a solution to the system that does not contain titanium dioxide.”)

nano material
Big Bang: Michael Dunning—Science Source; Steel,Transistor & Revitalift: SSPL—Getty Images; Feynman: Joe Munroe—Hulton Archive/Getty Images; Buckyball: Laguna Design—Science Source


A Vast and Growing Market

Over the past decade the use of nanoparticles has become pervasive, and exposure to them inescapable. Everyone agrees that the nanomaterials market today is vast, but there is great discrepancy among experts on just how big it really is. Some analyst reports put the size of the industry in the single-digit billions. The Project on Emerging Nanotechnologies estimates that it’s $20 billion and that it will double in the next decade. And a report released last year by Global Industry Analysts, a research firm, states that the worldwide market for nanotechnology will reach an astounding $3.5 trillion by 2020. Likewise, the exact number of nanomaterials that has been created is hard to pin down, but it’s probably in the tens of thousands. What’s certain is that these tiny things are out there, in great number, in a lot of the things we buy, eat, and wear. But even as nanomaterials have proliferated, the scientists who work with them and the companies that use them in their products have begun to raise questions about their safety, and to realize that we are still in the early stages of understanding the consequences of our exposure. And while there has been a very public debate about the risk of genetically modified organisms in food, the question of nanomaterials has largely stayed out of the mainstream.

Mixed in a liquid, such as sunscreen or a lotion, titanium dioxide has very little chance of moving through skin and into the bloodstream, where it might cause problems. A face powder with titanium dioxide, however, presents plenty of opportunity for inhalation. And from the lungs it can then make its way into blood. That is the kind of thing that Keller was searching for when he began his study of nano titanium dioxide in 2012. What opportunities might arise for it to cross into our blood?

In his lab, Keller flicked on his sunlike lamps over lotioned-up pigskins and waited. After just a few minutes he and his students took the samples and put them into a suspension, then fed the suspension through a filter. The goal was to get a glimpse of what the nanoparticles would look like after a bit of sun exposure, to see if anything changed that would increase the possibility for nano titanium dioxide to slip into the bloodstream. Previous tests—from manufacturers and labs that work with the FDA and EPA—had proved that part of what made nano titanium dioxide safe in viscous mixes like sunscreens was the fact that the particles clustered and clumped, creating structures bigger than the individuals and therefore less likely to slip through skin. But no one had yet tested the effects of UV rays on the nanoparticles.

What Keller and his team found was troubling. After exposure, the nanoparticles in lotions, cosmetics, and sunscreens were no longer as clumped as before. Individual particles had broken off. And of those, many had become even smaller. Louise Stevenson, a graduate toxicology student who sometimes works with Keller, recalls, “It was definitely concerning.” Ten years ago the idea of engineering products with nanoparticles—or, taken as a whole and in more complex forms, nanomaterials—had the scientific community excited. “Now,” she says, “it’s kind of like, ‘Wait. Hold up.’ There’s been a shift.”

In the mid-2000s, amid breathlessly optimistic reports about the burgeoning industry, hundreds of consumer companies, as well as the government, began investing in the research and development of nanoparticles for their products. Researchers found that manipulating food molecules at such a scale can produce wondrous effects: more nutrients and vitamins could be packed into a smaller space. Increasing the surface area of salt particles at the nanoscale, for instance, would let foods stay tasty with less salt. The structure of mayonnaise (which is itself a nanoparticle—an emulsified mixture of oil, water, and fat) could be tweaked to remove the fat. SABMiller began using clay nanoparticles, which were already common in ceramics, to make the walls of its beer bottles smoother, keeping beer fresh for longer. Nanoparticles began to be used in pesticides and even to deliver antibiotics via animal feed.

Many personal care products, such as toothpaste and sunscreen, contain 1% to 10% nano titanium dioxide by weight. Inset: Titanium dioxide is one of the most common whiteners on the market and, when sized properly, is an inert and naturally occurring metal. At nanoscale, however, it can cause problems. Even eco-friendly Tom’s of Maine, owned by Colgate-Palmolive, says that it’s used solely to “improve the aesthetic of toothpaste.”Photo by Sam Kaplan for Fortune; Inset: Eye of Science/Science Source

As questions have begun to swirl about the long-term effects of nano science, however, many companies’ interest has cooled. Nestlé and Heinz have publicly stated that, while keeping an eye on industry developments, neither is “actively participating.” McDonald’s, which had packaging that contained nanoparticles, has publicly condemned their use in its products, toys included. Bayer also shut down its nano research in 2013. Out of dozens of companies contacted for this story, none claimed active involvement in placing nanomaterials in the food chain.

This whiplash-inducing turnaround is a result of the fact that enormous amounts of money were poured into creating new materials before anyone knew quite what nanoparticles did once they got out into the world. Of the $1.8 billion earmarked for nanotechnology R&D by the federal government in 2011, for example, just $117 million went to safety research. It is telling that, as far back as 2009, representatives from Cargill, speaking before a U.K. parliamentary committee, said that until there was “a clear science-based regulatory regime” that could properly assess the environmental, health, and safety impacts, the company “will not incorporate internationally engineered nanomaterials into its products.”

Finally putting together that assessment is where Keller comes in. He is among some 120 researchers involved with the Center for Environmental Implications of Nanotechnology. Center is a misnomer, for the scientists, lawyers, economists, and doctors who make up CEIN are spread out across two continents—from the University of California (in Los Angeles, Riverside, Davis, and Santa Barbara) to Rice University, Duke University, and a group in Germany. The center’s mission is simple yet sweeping: “to ensure the responsible use and safe implementation of nanotechnology.”

It is playing an almost Sisyphean game of catch-up because nanoparticles have existed since the beginning of the universe, and humans first created them when we made fire. We’ve been churning out various new nanomaterials since the 1940s, often unwittingly. They were first used intentionally as reinforcement material in fighter planes, then in circuit boards, tires, fiber-optic wire, nondairy creamer, Tupperware, and, since at least the 1990s, cosmetics.

Today nano-size particles appear in paint, food, food packaging, washing machines, and clothing. The nano-materials industry touches nearly all aspects of manufacturing, from fertilizer for agriculture to the most targeted of medical technologies. It’s hard to know exactly what has a nanomaterial and what does not, though, because nanotechnology is still considered a trade secret in the U.S., and as such many of its uses go unlabeled. Even the Project on Emerging Nanotechnologies Consumer Products Inventory, established in 2006 as a way to track engineered nanomaterials entering the marketplace, is a guesstimate. Its creator, Andrew Maynard, director of the University of Michigan’s Risk Science Center, says his list provides a useful but only qualitative sense of what’s being used where.

However, the basic task of CEIN is even more fundamental than cataloguing which consumer products contain nanomaterials. It’s to answer this question: Now that they’re everywhere, what is it that makes some nanomaterials potentially harmful and others not?


Weird Things Happen at the Atomic Scale

Size matters. In the billionth-of-a-meter scale, things turn decidedly atomic. The very nature of the material shifts, not just with relatively slight changes in size but in its very shape. Such geometry is vital when considering stuff so small. Even slight changes to minuscule matter may have very large consequences. Defining the size of what constitutes a nanomaterial wasn’t internationally agreed on until 2011. Even the simplified version of the definition—anything with “one or more external dimensions” between one and 100 nanometers—is opaque and confusing, for nanomaterials can and often do shape-shift, as under UV rays, or inside cells, or out in the environment when interacting with other small particles. And particles larger than 100 nanometers often display nanolike qualities, meaning they act as strangely as the slightly smaller particles do. Ground zero for determining just how those changes might cause harm is UCLA’s nanotechnology lab.

The facility looks like pretty much any other lab. It’s mostly white and beige, with plenty of pipettes and beakers scattered about—only the beakers are quite small, and the machines they go in are quite large. Tian Xia, an assistant professor of medicine with a Ph.D. in biophysics, oversees much of what comes in for study. Nanoparticles most often arrive as a powder, but sometimes they come suspended in a liquid. They may be provided by major wholesalers, like Fisher Scientific and Sigma-Aldrich. They can also come from companies like DuPont. A gram of the latest and greatest nanomaterial of all, graphene, costs about $1,000.

Whenever a new shipment arrives, Xia and his team essentially ignore what’s on the label because it’s often not totally correct. Inside the jar the sizes and shapes vary, “and that affects the properties hugely,” Xia says. So they do their own analysis of what is in the jar before they even begin running tests in earnest. That’s what all the big machines are for: They’re electron microscopes. Lately fewer of the nanoparticles at the UCLA lab come from outside companies, and more are made from partner labs. The boutique lab-only nanoparticles may not perfectly reflect what’s on the market, but they are easier to work with because they are standardized. And the goal is to establish baselines.

UCLA CEIN, Nano lab
A zebrafish colony (top) in UCLA’s nanolab. Researchers harvest zebrafish embryos (middle) and screen them for nanomaterials using a robotic system (bottom).Photos: Courtesy of UCLA—Center for Environmental Implications of Nanotechnology

The most important baseline is toxicity, which is entirely relative. Toxicologists are fond of saying that it’s not the substance that kills, but the dose. Even water can be toxic in large quantities. To gauge toxicity, then, Xia and his team measure newer nanoparticles against well-known and heavily used ones. In cells, titanium is at the least harmful end of the spectrum, even though variations of titanium, such as dioxide, may well cause problems. Zinc oxide—another common ingredient in sunscreen—is at the harmful end.

One of the primary ways the scientists at UCLA test toxicity is to put a solution of the nanoparticles in with an individual zebrafish embryo, then track the development of the fish. This way Xia and his team might better understand “if there’s an effect in the water source” and what that means to living creatures. A zebrafish is, obviously, a far cry from a human, but the cell biology of all living creatures is relatively similar in such early stages of development. What’s harmful to a zebrafish will almost certainly be harmful to many, many other living things. Zebrafish embryos develop quickly, are easy to work with, and are standard in labs throughout the world. After just a few days the results are apparent, and often startling. After three days, a normal healthy zebrafish should hatch from its embryo. Often, in the presence of nanoparticles, it doesn’t.

During a visit to the UCLA lab one member of Xia’s team, a CEIN researcher named Sijie Lin, pulls up a range of snapshots on a grid, displaying the embryonic development of 16 eggs over 120 hours. Each egg started at the same point and continued apace until hatching began. Some of the eggs began breaking as tiny zebrafish escaped. Others became darker and darker. Some eggs, near the end, appeared entirely black. Lin explains that the nanoparticles had been interacting with an enzyme meant to break down the envelope surrounding the zebrafish—the “shell” of the egg they’re developing in. In normal development, and in solutions with nonharmful nanoparticles, the envelope dissolves enough for the fish to break free. In other cases, as with zinc and some silver and copper oxides, the fish is developing as it should, but it can’t break free. It’s trapped in the egg and dies there.

“So,” says Lin brightly, “we have a material property linked to an environmental hazard.” Nanomaterials, he explains, have different properties. But it’s not clear what’s causing the biological effects observed in the zebra-fish. “If we know the properties of the particle, we might be able to modify the manufacturing process, make it similar to what isn’t harmful, and the effect will be gone,” he says. “Eventually, in theory, it should be safer.” He’s just not sure when exactly, or how this safety breakthrough will come. Lin and Xia are in the process of identifying problems—they’ve catalogued and ranked by toxicity about 100 nanoparticles so far—and can envision finding a solution. But there is no clear path. Such is the state of nano science today.

Exactly how an individual nanoparticle becomes toxic—what it does to a cell—is hard to predict and often varies particle to particle. There are, however, a few properties common to a range of particles that appear to be responsible for a lot of toxicity. Positively charged particles, for example, are more likely to disrupt cell membranes, because the membranes are very slightly negatively charged. Nano-size rare-earth oxides, Xia explains, are “even wackier” and enter the lysosome (an enzyme-carrier organelle within animal cells) and change shape from spherical to “sea-urchin-like.” Xia smiles while describing what occurs when nanoparticles enter cells, his eyes wide with wonder over the tiny strangeness of it all. “Weird things happen that we never even thought would be possible,” he says.


GMOs Provide a Cautionary Tale

In 2011, just a few months after an international definition of a nanoparticle was agreed on, the Environmental Protection Agency released a remarkable report that stated, in effect, that it had no idea what was going on with nanomaterials and was not equipped to regulate them. The report was the result of a proposed EPA policy to “identify new pesticides being registered with nanoscale materials.” But “after minimal industry participation in a voluntary data-collection program,” the agency had thrown up its hands and recommended that reporting be mandatory. The EPA added that even if such industry reporting were mandatory, it still would have no idea what was going on, because the EPA wasn’t even sure what nanomaterials it should be worried about.

A year later the Food and Drug Administration drafted a proposal outlining potential regulation on nanoparticles in food, admitting that the particles “raise new safety issues that have not been seen in their traditionally manufactured counterparts,” while also saying that testing for such particles should be “rigorous” yet voluntary. Both the FDA’s and the EPA’s gestures are pretty much meaningless, however, because a lot of the manufacture of nanomaterials used in the most common consumer goods has—like much of the rest of the process—moved to China, Taiwan, Vietnam, and South Korea.

Consumers should be wary, but workers who handle nanomaterials should be concerned. The National Institute for Occupational Safety and Health has created maximum-exposure guidelines for nanoparticles, but those, too, are voluntary. A case report published by the American Journal of Industrial Medicine featured a story of a worker who developed nasal congestion, postnasal drip, facial flushing, and “skin reactions” after she was unknowingly exposed to a few grams of nickel nanoparticles “in a setting without any special respiratory protection or control measures.” There is simply no way to know how many workers are exposed each day, to how much or for how long, because as the EPA and FDA make clear, there is no law requiring disclosure. The most comprehensive study thus far of potential exposure to nanomaterials in the workplace was a voluntary survey conducted in Germany. Less than a third of all companies contacted even replied.

All this may sound a bit alarmist. But perhaps the most concerning and harmful aspect of heightened fears about nanoparticles is the potential for a broad, ill-informed backlash. Go to Google and search “nano” and “food” and you can find hundreds of articles from well-intentioned consumer advocacy groups making dubious scientific claims, scaring people away from buying half the products on store shelves.

Doctors and scientists have already accomplished remarkable things using nanomaterials to, for example, deliver highly targeted drugs to specific areas of the body and root out cancerous cells. Antibacterial nanoparticles like silver and copper are, when used properly, undoubtedly responsible for limiting the spread of disease. A new tool for fighting cancers and viruses is a nanoscale explosive nicknamed a buckybomb, which can reach a temperature of 7,232° F and attack exactly what needs destroying inside the body without harming the surrounding cells. Nano-scale technology has amazing promise. But the scientists trying to figure out what is potentially dangerous and what isn’t are the first to point out that industry is doing itself no favors by being opaque about just what has nano and what does not.

The history of genetically modified organisms provides a cautionary tale. “The last thing we want is for this to go the way of GMO,” says Keller. GMOs loom large for Keller and plenty of others in the nano community because they developed in a similar way to nano-materials. GMOs have existed on earth for eons; humans have controlled the gene pools of plants (like corn) and animals (like dogs) for millennia. But as modification ramped up, moved into labs, spread to more plants and animals, and became controlled by corporations, the science behind genetic modification grew murky in the public eye. And such darkness fed mistrust and fear. Now plenty of otherwise reasonable people go out of their way to avoid GMOs when the science has proved them safe.

Keller often speaks at conferences around the world to outline his work and explain some of the concerns raised by the proliferation of nanoparticles in the environment. Whenever he gives a talk, a segment of the audience—the nonscientists usually—goes from having no idea of what nanoparticles are to being deeply paranoid about them. But people are much more sensitive to some uses than to others—and intuitively savvy about unnecessary uses of the science. Keller says he wants to conduct a consumer survey on nanomaterials that includes a sort of cost-benefit analysis about where nanoparticles should and shouldn’t be used. He suspects that medical uses will get high marks, while food will score very low. “When you tell people, ‘This is there to brighten your food,’ they aren’t dumb, and aren’t thrilled,” Keller says. If consumers are given the proper information, along with smarter regulations and better labeling, Keller thinks they will make the right choices. The last thing he’d want to see, he says, is people no longer using sunscreen because they’re worried about nanoparticles inside. The risk of skin cancer from UV rays almost certainly outweighs any of the long-term risks posed by nanoparticles. The challenge ahead for Keller and his peers is determining how much nanomaterial is free in nature now, where it’s building up, and what might happen to it over the decades and even centuries.

To illustrate what can happen to the toxicity of nanoparticles in the environment, Keller likes to tell a story involving pesticides. Several large companies, DuPont among them, explains Keller, have started using nano-capsules to deliver small amounts of pesticide over time. It’s “a smart way to do it,” Keller says, safer and more targeted, as well as less wasteful. But like traditional pesticide, a lot of this nano-cide gets washed away, and wastewater-treatment plants can’t handle nanoparticles. So the pesticide ends up in sludge, which is rebranded a “bio-solid.” It’s then put back onto land, where it works its way into soil and attacks nitrogen-fixing bacteria, a crucial part of plant growth. If we fully knew where nano-pesticides were being used, we might stop the cycle or alter it and save both the soil and the crops.

Stevenson, the graduate student who often works with Keller, says she gets frustrated with the needless proliferation of nanomaterials. When she discovers a new product that has nanoparticles in it, she often thinks, “That’s just stupid,” because it’s so unnecessary. For instance, a recent trend is to put nano-size silver ions in sporting equipment, like shirts, to combat odor. “If you’re going to work out, you’re going to stink—it’s that simple. Why increase the risk of exposure?” she says. It may be decades before we can truly measure the cost of making our laundry hampers a little less pungent. 

This story is from the March 15, 2015 issue of Fortune.

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