It’s the Little Things That Matter

The FDA announced last week it will hold a public meeting this fall to gather information about developments in uses of nanotechnology materials in FDA-regulated products.

Meanwhile, Germany's Federal Institute for Risk Assessment said its recent investigation into 97 cases of "intoxication," some of them reportedly severe, in people who had used Magic Nano -- a household glass and ceramic tile sealant in an aerosol can -- was inconclusive. The product, which is not sold in the US, has since been withdrawn from stores in Germany. Officials there said they assume inhalation of the aerosol droplets caused the reported respiratory problems but that they cannot rule out whether the nanoparticles it contains also contributed to them.

Also this month, the Project on Emerging Nanotechnologies (a partnership between the Woodrow Wilson International Center for Scholars and the Pew Charitable Trusts), Rice University, the International Council On Nanotechnology (ICON) and Environmental Defense (a New York-based environmental research and advocacy nonprofit) co-sponsored a workshop on engineered nanomaterials and human health hazards. ICON, a coalition of academic, industrial, governmental and civil society organizations, is administered by Rice University's Center for Biological and Environmental Nanotechnology (CBEN).

At the workshop, a multidisciplinary group of more than two dozen scientists was asked to address two questions: "In light of the special physical, chemical, and biological properties of engineered nanomaterials, what information is needed to assess the human health hazards of nanomaterials that are currently in or likely soon to reach commercial production?" and "How can information needed to assess [such hazards] be obtained most expeditiously and efficiently?" A report with outcomes of the workshop will be published later this year.

Nanotechnology, a branch of science devoted to the design and production of extremely small matter, is described by the National Nanotechnology Initiative as "the understanding and control of matter at dimensions of roughly 1 to 100 nanometers (nms), where unique phenomena enable novel applications." (A nanometer is one billionth of a meter; a human hair is roughly 100,000 nms wide.)

'Great Potential'

According to an FDA statement, "Due to the small size and special properties of nanotechnology materials, they have great potential for use in a vast array of FDA-regulated products. These small materials often have physical or chemical properties that are different than those of their larger counterparts. Differences include altered magnetic properties, altered electrical or optical activity, increased structural integrity, and enhanced chemical and biological properties. These differences have the potential to lead to scientific advances. For example, nanotechnology could be used to create new drug formulations and routes of delivery to previously inaccessible sites in the body." (See also Photonics.com, Buckyball Causes Brain Damage in Fish)

The FDA said it is holding the meeting to further its understanding of developments in nanotechnology. In a Federal Register notice this week announcing the meeting, it asked for comments from those interested in presenting at or attending the meeting.

Specifically, the agency wants to hear about new types of nanotechnology products under development in the areas of foods (including dietary supplements), food and color additives, animal feeds, cosmetics, human and animal drugs and human biologics and medical devices; about any "specific scientific issues related to the development of these products relevant to FDA's regulation of them"; about "other issues about which regulated industry, academia and the interested public may wish to inform FDA concerning the use of nanotechnology in FDA-regulated products; and if there are opportunities for the agency to "address hurdles that may be inhibiting the use of nanotechnology in medical product development."

The need to improve understanding of nanomaterial hazards was highlighted by the reports that Magic Nano led to more than 100 calls over a 10-day period to poison control centers in Germany, Switzerland and Austria and to the product maker from people experiencing respiratory problems.

Magic Nano was first sold in German supermarkets and discount stores in late March. It was recalled by the manufacturer, Kleinmann GmbH (a subsidiary of Illinois Tool Works) after BfR issued a product warning on March 31. Between March 27 and 30, 97 people who reportedly used the aerosol spray claimed to suffer from health problems from trouble breathing to six cases requiring hospital treatment in which water accumulated in the lungs (pulmonary edema).

The product was very quickly withdrawn from the market, and consumers were warned not to use it. An alert sent out by Germany's Federal Institute of Risk Assessment (BfR, for Bundesinstitut für Risikobewertung) said, "The relevant regional authorities and toxic control and treatment centers of the federal states have issued warnings about two products which were sold in Penny stores, according to the manufacturers. The distributors have launched a recall and advised against using the sprays. As the exact cause of the health disorders still has to be established, BfR advises all consumers who have already purchased nano-sealing sprays on a propellant base, not to use them in confined spaces."

Experts from German poison control and treatment centers, science, industry, federal state authorities and the Federal Institute for Risk Assessment met on April 7 to analyze the cause of the intoxication cases from the sealing sprays. The incident was also recorded in RAPEX, the European rapid alert system for non-food products.

The Washington-based Woodrow Wilson International Center for Scholars said in a statement last week, "Despite meetings between BfR and the manufacturer, clear information on what is in the product and how Magic Nano was tested for safety is still lacking. According to BfR, it is possible that the reported health effects were associated with very fine airborne droplets produced by the aerosol product."

The aerosol was the only product in the Magic Nano line that was not actually produced by the company, but by one of its suppliers, the name of which was not disclosed. According to press reports, Kleinmann suspects it is not the nanotechnology that is at fault, but the anticorrosion liquid inside the aerosol.

The BfR said, "The distributors of the two sealing sprays were unable to supply the full formulations because information was missing from their upstream suppliers. A definitive toxicological assessment of the acute pulmonary disorders following use of the two products was not, therefore, possible in the scientific discussions."

Droplet Size is Key

The agency said that it does know from intoxication incidents involving "classical impregnating sprays" in Germany, Holland and Switzerland that the products do not cause severe health problems like respiratory distress or pulmonary edemas until they penetrate the alveolar tissue in the lung. In order to reach these areas, it said, the droplets must be very small.  "This droplet size is only achieved when the product is applied using a propellant and a correspondingly small nozzle in the spray head," the BfR said. "When, however, these liquids are applied using a pump mechanism, the droplets are no smaller than 100 µm and do not reach the alveolar tissue."

According to the BfR statement, the German experts said they assume that the observed health disorders were caused by inhalation of the very fine aerosol spray. "Aerosol sprays with a droplet size of 10 µm are only formed when the product is applied from spray cans containing a propellant," the BfR said. "Droplets of this size penetrate deeply into the lungs and can impair pulmonary function. The experts also pointed out that a classical toxicological assessment of the individual components in a product is not enough when the product is applied in an aerosol spray containing a propellant. Physical characters like the droplet size of the spray are the main deciding factors whether and, if so, which toxic effects could occur in the respiratory tract."

It said experts do not rule out the possibility that "the toxic effects observed in connection with the application of the two nano-sealing sprays containing a propellant during the period in question may have been caused solely by application as an aerosol spray. As it is not known whether nanoparticles in the aerosol also reached the patients' lungs and damaged the alveolar tissue, a possible involvement of these particles has to be elucidated."

Andrew Maynard, science advisor to the Project on Emerging Nanotechnologies, is an internationally recognized expert on airborne particles. According to Maynard in a press release from the project, aerosol sprays can produce respirable particles a few µms in size that can remain airborne for long periods of time and can reach the sensitive deep lung if inhaled. Once deposited, there is the possibility that chemicals or nanoparticles (if present) in the droplets can cause damage.

Last month, the Project on Emerging Nanotechnologies issued the first public, online inventory of more than 200 consumer products that manufacturers claim are made with nanomaterials or that use nanotechnology (www.nanotechproject.org/consumerproducts). Ten products in the inventory are described as "sprays," but most are pump-action sprays. Magic Nano is the only known, maker-identified nanotechnology product available to consumers in the form of an aerosol can.

"Pump-action sprays typically form droplets that are much larger than those from aerosol cans," said Maynard. "These are less likely to reach the sensitive deep lung when inhaled."

'Wakeup Call,' Nano or No

Irrespective of whether the "nano" here is the root of the health problem, a contributing factor or a false lead, Maynard said, he sees this incident as a wakeup call.

"Other companies using or hoping to use nanotechnology should take note: Without greater transparency on what nanomaterials are being used, how their safety is being evaluated and appropriate research into nanotechnology's potential human health and environmental impacts, it is difficult for consumers and policymakers to separate the responsible companies from the less responsible ones, and the safe nano-products from the potentially harmful ones."

Andreas Hensel, president of the BfR, said, "These incidents have demonstrated that the introduction of new technologies in consumer products must be coupled with an assessment of the possible risks arising from their use. It is incumbent on science to communicate this message to consumers, as well."

The German experts agreed that the health effects of products in the form of propellant sprays can only be determined in a test that simulates real application conditions indoors. Toxic effects only occur when the product itself -- i.e., the entire substance mixture in the formulation -- is inhaled as a fine mist with a corresponding small droplet size. This applies both to products with and without nanoparticles, the BfR said.

"The manufacturers of propellant sprays should, therefore, undertake and document toxicological tests of this kind before placing products on the market," according to the BfR's statement. "Only then will they comply with the requirements formulated in the Equipment and Product Safety Act, which stipulate that 'in the case of correct use or foreseeable incorrect use, the safety and health of users or third parties are not endangered.'"

In the US, ICON released a statement on April 10 about Germany's Magic Nano health scare. It said, "The recall is an important reminder of the need to be vigilant about product safety, regardless of the technology, and to take immediate action to protect public health when health effects are discovered. We support the producer's decision to recall the product.

"Although its name suggests it is a product of nanotechnology, a spokesperson for Germany's Federal Institute for Risk Assessment (BfR), which initiated the recall, expressed doubts about whether there is any 'nano' in the product at all," ICON said. "Without knowing the cause of the reported health effects, it is premature to assign blame to a specific ingredient or class of materials. This recall highlights the need for clarity with respect to terminology, hazard identification, cause and effect, and risk communication. We urge the regulatory authorities to complete their investigations before drawing conclusions about the health risks of other products based on the health effects of Magic Nano. We urge companies introducing products to the marketplace to engage in thorough safety reviews of their products before going to market, regardless of whether or not the products contain nanomaterials or other products of nanotechnology."

Nanorisk Management

ICON recently awarded $55,000 to researchers at the University of California, Santa Barbara (UCSB) to conduct a "Review of Best Practices for Nanotechnology Safety."

Kristen Kulinowski, executive director of Rice University's CBEN, said, "ICON is working to document current practices for identifying, managing and reducing risks -- across all life-cycle phases -- for the production, handling, use and disposal of nanomaterials. Our goal is to identify the safest way to work with nanomaterials, and to do that we need to identify the best approaches in use today by industries that are already developing and using nanomaterials."

The best practices initiative is intended to help companies manage potential nanotechnology risks with more certainty. ICON also hopes it will help inform risk management efforts that are underway at the National Institute for Occupational Safety and Health, the Environmental Protection Agency and other US federal agencies.

The project leader at UCSB is Patricia Holden, professor of environmental microbiology. The team includes Magali Delmas, assistant professor of business policy; Richard Appelbaum, professor of sociology and global and international studies; and Barbara Herr Harthorn, research anthropologist and co-director of UCSB's NSF Center for Nanotechnology in Society.

Work at UCSB will proceed in two stages. The first involves a comprehensive review of all existing "best practice" development efforts. In the second stage, the researchers will interview a wide variety of companies internationally to determine current practices. One of their major goals will be "to identify critical needs for the standardization and implementation of safe practices in the nanotechnology industry in different parts of the globe." ICON plans to make the results of the project public by the end of the year.

Harthorn said, "The ICON-funded study will provide essential data on current nanotech industry standards and practices for enhancing the environmental and health safety of nanomaterials. By providing comparative data on companies in the US, Europe and Asia, it will help shed light on new safety models as they are being implemented and also help identify where they are most needed."

Registrations for the FDA's fall meeting are not yet being accepted, but those who wish to attend or present at the meeting may send "expressions of interest" to Poppy Kendall at [email protected]; phone: (301) 827-3360. Comments may be submitted to the Division of Dockets Management (HFA), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. All comments should be identified with Docket Number 2006N-0107.

The FDA said it will obtain a venue and structure the meeting based on the responses. Meeting details will be provided in a Federal Register notice later this year; for updates, visit: www.fda.gov/nanotechnology.

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