Toxicology Down in Whoville: Who's testing nanoparticle toxicity?

My daughter is rehearsing to be a Who down in Whoville, a creature invisible and nonexistent to all but Dr. Suess’s Horton who first hear the Whos. This would make her and her fellow Whos, inhabitants of a world the size of a dust mote, nanoparticles I suppose, which according to at least one definition are particles smaller than 100 nanometers (or one billionth of a meter). Around the time Dr. Suess was envisioning the importance and potential of the nanosized Whos, Dr. Richard Feynman, the Nobel Prize winning physicist was also envisioning the technological potential of the very small, well before the term nano-anything even existed. Towards the end of a 1959 lecture, Feynman offered a $1000 reward to anyone who could figure out how produce a nearly Who-sized version of the Encyclopedia Britannica, shrinking the entire series so could fit on the head of a pin.

Though Feynman expected rapid progress, the technological breakthrough (and a legitimate claim for the reward) didn’t come for another thirty years. But since then, the production of nanoparticles, and the field of nanotechnology has blossomed. One institute, Foresite Nanotechnology offers a Feynman Grand Prize of $250,000 for “the first persons to design and build ...a nano-scale robotic arm and a computing device….” By some estimates, nanotechnology is now a billion dollar field, involving both government and industry dollars and it’s growing. The promise of nanotechnology includes both environmental and health applications including more effective drug delivery, potential applications for solar derived power, reduced use of industrial chemicals, and improved environmental cleanup methods.

Until researching this article I had thought the emerging field of nanotechnology would be a great opportunity to witness the fruits of over thirty years of experience with environmental standards, guidelines, laws and regulations. I had thought that development of nanoparticles and nanomaterials (made of nanoparticles) would go hand in hand with human health and environmental toxicity testing. That we would avoid yesterday’s and today’s problems like PCBs, lead paint, and climate change, so that today’s little Cindy-loo Whos won’t need to ask, “How did you let this happen, and how do we fix it?”

Unfortunately, it seems that the Whoville cats have already left the bag. According to Dr. John Balbus of Environmental Defense, the production of nanomaterials has already outpaced knowledge of human health and environmental impacts.

“The Wilson Center [Woodrow Wilson International Center for Scholars] notes 356 nanoparticle products on the shelves around the world,” says Balbus, “and most of them have virtually no in-depth toxicity testing done on the basic material in them…..There are huge knowledge gaps about how these materials will move about and persist, whether they will bioaccumulate, let alone their toxicity to humans or other animals.”

Whoops. What about those thirty years of regulations and guidelines and experience? What about all those toxicity testing techniques designed to protect human health and the environment? After decades of data on thousands of chemicals, one cannot argue that we’re not better off today than we were thirty years ago, but there are also plenty of chemicals that we still just don’t know enough about. And nanoparticles are like the new kid on the block who doesn’t play by the rules, and that’s what makes them so intriguing for industry. In many cases nanomaterials are just different from their counterparts (including both their basic atomic building blocks, and their larger composites – both of which may or may not have already been through all the toxicity testing hoops).

“Ordinary new chemicals go through a series of [initial] screens using computer-based structure-activity-relationships,” explains Balbus, meaning that to some extent researchers and regulators can predict the activity of a chemical based on its structure, comparing the similarity of that structure to chemicals of known toxicity, allowing regulators to determine the need for further more detailed toxicity testing.

“With nanomaterials, we don’t have the experience to be able to predict, so they can’t go through the same screening tests…the tools to use for regular chemicals don’t apply to nanomaterials.”

Titanium dioxide is an example of a chemical with a long history -- dating back to the early 1900’s -- of mass production (now millions of tons per year) in non-nano form, and a more recent history of mass production as a nanomaterial. Traditionally one of the most important white pigments in commerce, one new use for nano-sized titanium dioxide is as a next generation sunscreen, ironically labeled “non-chemical.” Ever wonder how those new sunscreens with titanium and zinc oxide protect you from the sun’s ultraviolet rays without making you look like a clown? Turns out that the typical white smear associated with titanium or zinc oxides result from the excellent light scattering properties of these chemicals. But nanosized particles of titanium dioxide allow visible light to pass through them and so appear clear, while still scattering the sun’s shorter and harmful ultraviolet rays. And, while many in the field agree that a sufficient number of studies on dermal or skin toxicity of nanosized titanium dioxide have been conducted, the same cannot be said of ecotoxicity studies evaluating the potential impacts on the environment.

Although the pending large scale production and potential release of nanoparticles like nanosized titanium dioxide is a recent development, nanoparticles or ultrafine particles have existed in our atmosphere ever since there were fires, volcanos and sea spray to produce them. More recently, manmade sources including traffic and industry have added to the suite of nano-sized particles in the atmosphere, and higher amounts of particulates in the air are consistently linked with adverse health impacts such as increased death rates and respiratory distress. The most recent studies suggest that ultrafine particles cause the greatest harm to the lungs.

In the lungs, says Dr. Vicki Stone, of Napier University, Edinburgh, Scotland, “Smaller particles almost always induce greater cellular response than larger particles of the same chemical composition. Such responses include cell death, and responses that cause activation of inflammation (immune response) and pathways that drive disease.”

In general as particle size gets smaller the toxicity increases, in part because of increased surface or reactive area, and in part because the behavior of the chemical in the environment or in living systems might change.

For example, nano-sized forms of chemicals that normally would not be able to cross into the brain (blocked by what is know as the blood-brain-barrier,) might be able to penetrate and gain access more easily. Similarly nano-sized particles may act differently in the environment. Perhaps becoming more easily dispersed than their counterparts, or perhaps just the opposite, sinking into sediments or settling on soils, making them more likely to be ingested by critters that make a living by stripping chemicals from sediment and soil particles.

However, cautions Stone, “Only a relatively small number of particles of different chemical composition have been tested…so many experiments are needed to verify whether this is a general phenomenon.”

In many cases, whether a product is tested for toxicity and how it is tested depends on the product, the potential for exposure, the amount in production, the proposed end use. For example, a product may be classified as a pharmaceutical, a food additive, a pesticide or a “device” such as a washing machine that sanitizes clothes as it washes, by releasing silver ions and perhaps some nanoparticles as well, (yes there is such a thing, and EPA is currently struggling with how to classify it.) The regulations, standards and guidelines that govern the use and release of a particular chemical may consider all of the above, and this is where a chemical, or an altered form of an existing chemical, may slip through the regulatory cracks.

Fortunately, the US EPA along with several other government agencies, acknowledging the different nature of nanoparticles and nanomaterials, have over the past five years, committed millions of dollars towards health and environmental effects research on nanomaterials; and they’re not the only ones.

“Large companies are certainly concerned about releasing toxic products and having liability risks,” observes Balbus, “so they have done some of the toxicity studies on nanoparticles…..but much of the development and commercialization is being done by small startups that don’t have the resources to do much toxicity testing or exposure testing.”

Stone agrees, “There appears to be huge variation in the way in which different companies are approaching the questions about testing nanoparticle hazard and risk – some have funded extensive research, others are waiting to see whether legislation will require testing, while others are avoiding using nanomaterials until they have a clear understanding of how they will be regulated.”

So, the question is, will the threat of regulation prompt responsible and meaningful health and environmental testing of nanomaterials by industry, heading off further involuntary regulation, or increased creativity in classification of nanoparticles? Let’s hope for all those Whos down in Whoville that it’s the former.