NANOTECHNOLOGY

Time to Sweat the Small Stuff

Nanotech Needs FDA Oversight (But They Knew That Already)

Who can forget the sci-fi scenarios that scientists so enthusiastically invoked when, a few years ago, they first pitched the potential benefits of nanotechnology—the science and engineering of vanishingly small stuff? Like the submarine in the popular book and movie Fantastic Voyage, microscopic robots hardly bigger than blood cells would someday cruise through our vessels, we were told, monitoring our health and nipping diseases in their very buds.

Well, nanotechnology is indeed making its way into medicine. But as might have been expected, it is doing so in more modest, albeit impressive, ways, scientists told a panel of Food and Drug Administration advisers earlier this week. Therapeutic powders for use in pills and capsules are being ground into nanoscale motes of medicine that are orders of magnitude smaller than the “micronized” powders widely used today—an advance that promises to speed absorption, increase effectiveness and perhaps even improve safety, since less of the drug may be needed in this form. Cancer medicines are being made so small that they can wend their way through tightly layered body tissues, giving them unprecedented access to their tumor targets. Before long, doctors may even have access to their first “theragnostics”—engineered nanoscale molecules that are both diagnostic (by glomming onto tumors and making those cancers “light up” on an imaging device, for example) and therapeutic (by destroying those tumors once they attach to them, and allowing doctors to monitor their demise).

But even as the first wave of novel nanoproducts is washing up on the FDA’s shores in the hope of gaining marketing approval, the agency is still trying to figure out whether its age-old criteria for determining the safety and efficacy of new drugs need to be upgraded to deal with this new world of nanotech. After all, nanoscale materials, which are generally between 1 and 100 billionths of a meter in size, or a few ten-thousandths the width of a human hair, are in many cases far more toxic than the same materials in bulk form. Indeed, the blessings of nano are also its curses. Nanoparticles will get into those tumors, for example, but they will also get into places you don’t want them to get. And when they get there, they will do things you don’t want them to do, because particles that size tend to be far more chemically reactive than the same materials in larger form. So FDA officials, along with their counterparts in other agencies dealing with their own versions of the nanotech revolution, need to figure out how to judge these new materials, and pronto.

Yet most have barely taken a nanostep.

As a sign of how slowly the FDA is moving to address this issue, consider that the main question that advisors scratched their heads over at this week’s meeting was whether the agency ought to craft some helpful “guidance” for industry, to tell companies the kinds of things they ought to consider as they start pitching their new nanodrugs for approval. Sound familiar? It ought to. It was the same question asked—and answered—by the FDA’s own Nanotechnology Task Force last year. The answer, by the way, was “yes.”

“The guidances the Task Force is recommending would give affected manufacturers and other interested parties timely information about FDA’s expectations, so as to foster predictability in the agency’s regulatory processes, thereby enabling innovation and enhancing transparency, while protecting the public health,” that task force concluded exactly a year ago today.

At this week’s meeting, advisors split fifty-fifty on the question, though there was nothing reassuring in the reasoning behind several of those who voted against crafting that guidance. That “no,” several said, was not a reflection of their confidence that the current system was adequate. Rather it came from their realization that no one has much of a clue what to look out for and what to tell these companies. That is a disconcerting sentiment from the agency that regulates the nation’s medicines, medical devices, food additives, and cosmetics (and don’t get me started on those last two categories, which are already heavily laden with nanotech ingredients with absolutely no approval from the FDA because food additives and cosmetics are effectively not subject to FDA oversight until after they cause harm).

Of course, we can hope that there is no particular risk to these products. We can hope that the slides presented to FDA advisors by Darin Furgeson of the University of Wisconsin-Madison, who is doing research on nanotoxicity, were misleading as they showed little laboratory fish developing abnormally after being raised in water spiked with small amounts of nanoparticles. “Some changes begin to occur,” Furgeson told the FDA advisors with nonjudgmental equanimity. Among his observations: “Their eyes began to get different shapes.” “Excess fluid around the heart.” “Even the number of vertebrae changes,” as does the curvature of the spine.*

This was not true for all nanoparticles at all concentrations. But perhaps most worrisome, experiments described by Furgeson showed that extremely minor differences in the size or structure of various nanoparticles can make big differences in their apparent toxicity, suggesting that this is not going to be an easy field to get straight.

Later I spoke to Frank M. Torti, principal deputy commissioner and chief scientist at the FDA, and mentioned that if I were a little more jaded then I might conclude that the FDA is going to keep asking the question of whether guidance is needed until it gets the answer that it and the industry wants. After all, while guidance is technically just a recommendation, it can be time consuming to craft and is seen by companies as added regulation. Torti urged patience. While it may be helpful, he agreed, to provide industry with some general pointers about how to assure their nanoproducts are safe, based on what little is known to date, it would be more helpful to have guidance a little later that incorporates findings from the research now being conducted by FDA and others.

“There is ton of stuff going on with nano,” Torti said of the federal research agenda. Meanwhile, he added, the good thing about how the FDA regulates is that, in the end, whether a company knows everything about how its product works or not, it has to prove that the product is safe in animal tests and human studies before getting permission to market it. So bad medicines of any kind are likely to get screened out.

I think that an assignment to write guidance on nano would force the FDA to focus, and give the topic the aura of urgency it deserves. But truth be told, the safety of nano in medicine is but a minor worry of mine compared to the equivalent safety challenges posed by nano for other regulators such as the Environmental Protection Agency and the Occupational Safety and Health Administration. At the FDA, at least, the rules are plain, at least at high altitude: Before being approved, a company must show that its product is safe and effective. There are going to be some questions about how to prove these things for nano-based medicines, but in the end, even if very little is known about why nanomaterials behave as they do, dangerous ones will hopefully be identified during the standard safety testing in animals and early studies in people.

Source: J. Clarence Davies, “Nanotechnology Oversight,” (Woodrow Wilson International Center for Scholars, 2008).

By contrast, safety rules under the authority of EPA and OSHA are in many cases written differently. Pesticides, for example, are regulated by EPA under the Federal Insecticide, Fungicide, and Rodenticide Act, or FIFRA, only if they are plainly advertised as pesticides. Thus the many products on the market that are loaded with nanoparticles of silver as a means of killing bacteria (thus preventing odors, for example, in the socks that are impregnated with that silver) today escape FIFRA regulation entirely by simply not claiming on their labels that the silver is there as a pesticide. “Big deal,” you may say. “Who wants to regulate a smidgeon of silver in socks, anyway?” Well, among others, engineers who run water treatment plants—who have complained that washing machine water laced with nanosilver threatens the survival of helpful bacteria that clean up the waste water flowing into their facilities.

Similarly, the Toxic Substances Control Act that the EPA uses to regulate various toxic chemicals typically allows companies to manufacture thousands of pounds of a chemical before that chemical is subject to regulation, on the assumption that such modest quantities can do only so much harm. But a mere pound of a chemical in nano form can be even more toxic than thousands of pounds of bulk material. Yet the law, as written, does not recognize this difference.

These and other glaring regulatory lacunae have been talked about for years, with nothing having come of it but a voluntary program, boldly promulgated by our protectors at the EPA, that asks companies to please, if they don’t mind, step forward and tell the agency what they are making. And don’t worry, dear companies, because we, the EPA, won’t tell the public what you tell us.

Surely we can do better than this. Nanotechnology is a radically promising new branch of engineering and ought to be given the best boost it can get. But just as a child does not benefit from free access to the cookie jar, the nano industry can only suffer in the end from a lack of reasonable oversight. As J. Clarence Davies, who served as an assistant EPA administrator under George H.W. Bush, said on Wednesday as he and the Project on Emerging Nanotechnologies launched their latest report on what is needed in the way of new nano oversight, “We’ve realized over recent years that if you’re going to have adequate markets, you’ve got to have adequate oversight.”

Davies’s excellent report spells out numerous nano-related regulatory lapses that the new administration should tackle ASAP. What good is it, he asks, to give workers OSHA-required Material Safety Data Sheets that spell out the toxicity of the nanomaterials they are working with, if the toxicity data contained in those sheets is based on studies of the materials in bulk form? We know that these substances have very different safety profiles on the nanoscale. Yet the law does not require the sheets to reflect this.

“That’s not okay,” Davies said. “It’s deceptive and misleading and does not give the necessary guidance to workers in terms of what kinds of precautions they should take.”

The United States should not blow its early lead in nanotechnology, a field that the Commerce Department has called “the next industrial revolution.” But to get it best, we’re going to have to get it right. The window of opportunity is still open. Now is the time to sweat the small stuff.

Rick Weiss is a Senior Fellow at the Center for American Progress and Science Progress.

* In response to comment #2, below, the text has been changed from “changing the curvature of the spine” to “as does the curvature of the spine.”

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