Chapter 12: Nanotechnology: Is It Safe? – NanoInnovation: What Every Manager Needs to Know

Nanotechnology: Is It Safe?

Nanoparticles have been part of our natural environment forever, yet historically we had little grasp of them or their health effects. Today, the tools of nanotechnology allow us to characterize and understand both natural and man-made nanoparticles and thus take a more rational approach to safety.

Youseph Yazdi, Ph.D., Department of Biomedical Engineering, Johns Hopkins University

As we consider what happens at the convergence of bio and nano, it is important to consider safety issues, especially where and how nanotechnology – especially nanoparticles – might potentially cause harm to humans, or to the environment.

In the realm of nanotechnology, safety is an issue that impacts everyone. As a consumer, you may worry that nanoparticles in a food product or cosmetic will cause cancer or some other disease. If you're an employer at a company whose products use nanomaterials, you worry about the safety of your employees who might inhale or absorb nanoparticles in the workplace. If you work in medicine or healthcare, you know that nanoinnovations need to pass rigorous animal and human clinical trials to confirm that they are safe as well as effective. As environmentalists, we all need to ensure that nanoparticles created to solve problems don't inadvertently cause problems when they are released into the environment. If you work in city government, you may worry about health hazards if nanoparticles that find their way into the sewer system and kill bacteria needed to biologically process wastewater. If you are working in the space program at NASA, you worry that nano- and subnano particles will penetrate the hull of a spacecraft and sever DNA strands while speeding through the bodies of astronauts bound for Mars.

From its inception, the nanoinnovation community has been extremely diligent and conscientious about studying and monitoring safety issues. This attention to risk factors has helped insulate the nanotechnology sector from media attention and public criticism. However, safety is an area that requires constant diligence since unpleasant surprises can emerge unexpectedly to reveal a hidden threat.

There is good reason to ensure that there aren't any lurking dangers embedded somewhere in nanoinnovations. In recent decades, the public learned that many products previously considered safe and marketed by reputable companies were actually unsafe, even fatal.

Asbestos was used as fire-resistant thermal insulation in construction for more than a century, and 30 years ago was confirmed to cause cancer even in minute quantities. The first generation of silicone breast implants leaked and caused debilitating diseases. Tainted livestock organs ground into a meal and fed to sheep and cattle conveyed a horrific condition called “mad cow disease” acquired by humans who ate contaminated meat.

Nanoparticles are used in materials, clothing, coatings, and even food products and packaging. Is there a hidden hazard lurking in one of these substances or applications?

In many cases, the safety issue may not be the hazard or toxicity per se, but the form of the material and how it is used. For example, asbestos is still used in ∼3000 products today, in products that include safeguards against inhalation of particles. A thicker more stable form of silicone is used in breast implants. Long carbon nanotubes (CNTs), which have an asbestos-like form factor, are used in applications that embed or encapsulate the particles to stabilize them, so they can't be inhaled. It is difficult to validate risk factors for nanoparticles, since many nanoparticles are beneficial in one application, but may be harmful in a different application, or when those nanoparticles are disposed of.

To some extent “toxic” is a relative term. Any substance that concentrates in a human organ can have a toxic effect depending on the composition, size, and shape of the particle. Any foreign particles introduced into the body can accumulate in organs and cause inflammation. If the particles concentrate in quantity, they can cause the body to encapsulate them, forming granulomas. Some anticancer drugs are more toxic than the nanoparticles used to deliver them.

So far, a few safety issues have been identified that involve nanoparticles, but, in general, nanoinnovations appear to be safe, although we don't know everything yet since the field of nanotoxicology is very young. The term “nanotoxicology” has only been in common use since 2004. The first notable uses of the term appeared in 2004, in commentaries by R.F. Service [1] and Donaldson et al. [2].

So far, only a few validated safety studies have confirmed serious health or environmental problems that are unique to nanoparticles. In most cases, the same precautions used for any small particles, powders, and aerosols have helped to prevent serious problems in the workplace or marketplace for nanoparticles.

The current consensus is that most nanomaterials and nanoparticles are safe. However, most regulatory agencies and experts in the field suggest that our knowledge of nanoparticle toxicity is still limited, more research is needed, and caution should be exercised in the handling and disposal of certain nanomaterials. A full life cycle assessment is recommended for all products that incorporate nanoparticles and nanomaterials.

12.1 Early Experience with Nano Safety

Humans have been exposed to nanoparticles for centuries. Airborne nanoparticles are contained in wood smoke, eruptions from forest fires and volcanoes, exhaust from cars and trucks, and particulates from furnaces used by factories and utilities.

People around the world are being exposed to nanoparticles every day. Pollution from burning fossil fuels generates a vast amount of particles ranging in size from nano to macro – as evidenced by the visible clouds of pollution that are still suffocating major cities in the world. In some heavy traffic areas, there can be as many as 5000–3 000 000 sub-µm particles/cm3.

Workers are exposed to nanoparticles in many industries. Miners have inhaled mineral nanoparticles as part of their jobs. Nanoparticles of carbon inhaled by coal miners contributed to black lung disease. Workers in many factories come into contact with nanopowders, aerosols, dust, and other materials that are hazardous. In most cases, workers use masks, filters, protective clothing, and ventilation systems to protect themselves.

In our daily lives, we consume millions or billions of submicrometer particles in our normal diet, including food additives such as titanium dioxide and aluminosilicates [3]. Popular condiments ranging from gum and candy to frosting can contain nanoparticles that are used to control color, consistency, or other attributes.

In the past decade, we have come in contact with hundreds of new products and materials or ingredients that are the result of nanoinnovation. We use materials that contain carbon nanotubes. We wear clothing treated with nanocoatings. We are treated with drugs that have been nanosized. We wash our clothes in appliances that have been coated with antibacterial coatings that are designed to release nanoscale silver ions. We may be exposed to nanoparticles through hair dyes, sunscreens, skin creams, and many other products.

Therefore, it makes sense to gain an understanding of the risk factors associated with nanoparticles. To do this, we need to understand the false indicators as well as the real indicators of risk hazards; we need frameworks to conceptualize and map these risks as well as ways to pool our information and collaborate across borders.

Reasons for Caution: The First Nanosafety Incidents

Public safety has always been a major consideration for nanoinnovators. For more than 25 years, public perception has played an important role in public debates over nanotechnology safety. The history of nanotechnology incidents contains a mix of misperceptions and false alarms, as well as verified health risks and toxicology studies.

In 1986, Eric Drexler coined the term “gray goo” in two paragraphs in his book Engines of Creation. The same year, the concept was featured in Omni magazine. This fueled a media debate about whether self-replicating “nanobots” could be unleashed on the world and spread like a virus to destroy humanity. In 2000, Robert Freitas coined the term “ecophagy” to describe how “biovorous nanoreplicators” could keep replicating themselves and ultimately consume entire ecosystems. These fears were vividly brought to life in Michael Crichton's 2002 book, Prey, which described nanoparticles that escaped from a laboratory to form self-aware, intelligent swarms that could take human form. The public debate and associated fears have diminished as scientists have refuted these possibilities. Today, most authorities consider the concept of nanorobots spinning out of control as somewhere between “absurd” and “cautionary.”

Another safety issue that was initially feared but never materialized was a potential public backlash against nanotechnology. In the 1990s and early 2000s, there was a legitimate concern that the public would reject anything “nano” just as Europeans initially rejected genetically modified crops and foods in the 1980s and required special labeling on GMO products. However, there was no significant backlash against nanotechnology despite the hidden nature of nanoparticles and materials. Several factors have made nanotechnology “friendlier” and more acceptable to the public than genetically modified foods.

First, the reaction of government regulators was mostly favorable. In the United States and many other countries, federal agencies adopted a policy of regulating nanoparticles like other materials such as paints and coatings, devices like semiconductors, and medical drugs – all of which were early product categories that integrated nanoscale materials and structures. Most agencies treated nanoparticles as “special forms” of the bulk substances they represented and relied on existing regulations for safe handling of powders, aerosols, or known toxins, rather than the unique properties of nanoscale materials.

This light regulatory treatment was aided by the fact that nanoparticles have been used in many products for a century or more. Well-known examples include carbon black used in automobile tires and photocopier ink, nanoparticles used in cosmetics since the 1960s, and nanocoatings in stain-resistant clothing since the 1970s. Carbon black has been used in rubber products for more than a century – today, more than 10 million metric tons a year are produced with no significant safety issues.

As previously discussed, nanotechnology also benefited from the favorable legacy of microtechnology. Microcomputers and microchips launched the digital revolution with few safety concerns. Microdevices from videogames to music players, everything electronic became smaller, more compact, and “user-friendly.” In 2005, Apple named its iPod music player the “Nano,” which sold a million units in 17 days.

This atmosphere of user-friendliness benefited “everything nano,” which was viewed by most people as an extension of “micro.” The public perception was that microtechnology gave us a myriad of innovations, and nanotechnology is a logical extension. Micro is a friendly word. Nano sounds even friendlier. In popular jargon, it means tiny and ultrasmall.

Also, it was helpful that nanotechnology was not associated with food products. As the first few hundred or so commercial uses were emerging in the 1990s, it was not widely known that nanoparticles were already present in cosmetics and other consumer products, so consumer concerns were minimized.

Despite this nano-friendly climate, there were a few notable incidents that received media attention that are important to mention, that any manager should know about.

The First Nano Safety Incident Was a False Alarm

The first reported safety scare attributed to nanotechnology was actually a false alarm. In 2006, a bathroom cleaning spray called Magic Nano was blamed for sickening 70 people in Germany. Half a dozen people were hospitalized for pulmonary edema. The product had been sold for 4 years as a pump spray with no reported problems. The health problems began when the product was introduced as an aerosol spray. In the pump spray the solvent was a liquid and did not evaporate, but as an aerosol product, a corrosion inhibitor that was added to the formula made the spray more volatile and caused particles to form in the lungs when inhaled.

Because the product had “nano” in its name, the media jumped on the story as the first example of an illness caused by nanotechnology. However, the name “Magic Nano” was misleading since it did not contain any nanoparticles as ingredients.

The incident was investigated by Germany's Federal Institute for Risk Assessment. Later it was discovered that the particles in the aerosol were not nanoscale in size, so this was a case of “aerosol poisoning” not associated with nanoparticles or nanotechnology. The misleading factor was the name of the product – Magic Nano – although there was nothing “nano” about Magic Nano except the name. The aerosol version of the product was recalled as soon as the health problems occurred.

The First Nanoparticle-Linked Health Incident

In 2009, seven Chinese women working at a paint factory where nanoparticles were used fell ill with a serious lung disease, and two died. The factory manufactured polyacrylate-based paint. According to reports, cotton gauze masks were the only protection used by the women in the workplace, which had no windows and was poorly ventilated. The machinery at the factory was shut down and no other people became ill. The women experienced itchy eruptions on their face and arms and fluid build-up around their heart and lungs. The symptoms were different from symptoms normally associated with paint inhalation. Also, the symptoms persisted after the women were no longer exposed to the paint [4].

A research study detailing the incident was published in the European Respiratory Journal [5]. The team was led by Yuguo Song, from the Occupational Disease and Clinical Toxicology Department at Chaoyang Hospital in Beijing. The team found nanoparticles 30 nm in diameter, deep in the lungs of the women. The particle clusters had formed pleural granulomas, which are ball-like collections of immune cells in the lining of the lung. These structures formed when the immune system was unable to remove the particles. The study reported that the symptoms came from inhaling fumes produced from polystyrene boards that were heated to 75–100 °C after being sprayed with a paste-like plastic called a polyacrylate ester.

“This is the first clear case where there is an association between someone breathing in nanoparticles in the workplace and getting seriously ill,” observed Dr. Andrew Maynard, former Advisor at the Woodrow Wilson Center's Project on Emerging Nanotechnologies, now NSF International Chair of Environmental Health Sciences at the University of Michigan School of Public Health [6].

Some toxicologists have suggested that nanoparticles per se were not responsible. The toxicity of the plastic material and poor health and safety conditions in the facility were major, if not primary, causes. Whether this fatal incident resulted from workplace conditions, the accumulation of particles, or from properties unique to the nanoparticles, is unclear. It is known that larger particles of different sizes and shapes can also cause granulomas to form. Which factors were most responsible for these unfortunate deaths and illnesses remains unclear.

12.2 What We Know about Nanoparticle Risks

In the past half decade, hundreds of research projects and papers have focused on nanosafety issues. Researchers have studied whether short or long carbon nanotubes can cause cancer (like asbestos fibers), and whether silver ion nanoparticles kill friendly bacteria and aquatic species if released into streams and reservoirs. These studies helped confirm what we can and cannot do with nanotechnology and provided the first guidelines for safe use of nanomaterials. Most major studies have focused on the impact of nanoparticles on human health, their impact on the environment (especially aquatic ecosystems), and the potential impact of discarded nanoparticles on biological waste treatment systems.

Ongoing medical research is exploring which particles and materials are toxic to human health, since nanoparticles have the ability to penetrate the membranes of cells that can produce a toxic effect, trigger an immune response, or produce an unexpected catalytic reaction. Some substances are safe at the microscale and larger, but become reactive and potentially toxic at the nanoscale. The size and shape of the particles may also cause medical problems. For example, a long carbon nanotube can act as a nanoscale knife, slicing DNA strands, which can cause cancer. Even the surface configuration of the individual particles can have an effect.

Environmental safety research has been underway since the early 2000s. Environmental researchers have been studying what happens to nanoparticles that may be safe in industrial or consumer products, but may deteriorate and become harmful after disposal. They are attempting to identify when nanoparticles may be an unintended by-product of an industrial process. Of special concern is the impact of nanoparticles on an entire ecosystem or food chain, and its unintended consequences.

Most nanoparticle safety research has involved toxicology studies on animals. Researchers have found that most nanoparticles are harmless and/or are removed by macrophages (white blood cells). On the other hand, some particles such as long needle-shaped nanotubes are not removed. Nanoparticles can accumulate and form granulomas in the lungs and other organs.

Nanoparticles can also be absorbed by plants and accumulate in their tissues and can accumulate in the food chain, which can affect the environment. The ability of the body to absorb and concentrate nanoparticles is used to deliver therapeutic nanoparticles in nanomedicine. But which types of materials and concentrations are toxic? The challenge for science is to identify which types of nanoparticles and accumulations can be harmful, and why.

Determining the “safety” of a nanoparticle can be tricky. Some nanoparticles are both safe and toxic. For example, it is ironic that the same nanosized silver used to coat surfaces in hospitals and clinics – to prevent the growth of bacteria – can also kill friendly bacteria and harm aquatic creatures if released into streams and reservoirs.

Given these dichotomies, the relevant question for nanotechnology is not “is it safe?” but rather, “what are the safest ways to use it?” Here are some examples of findings drawn from toxicology research that provide some early “safety signals” and also illustrate how complex and sometimes confusing this type of analysis can be.

Carbon Black Nanoparticles

Carbon black is a nanopowder form of carbon that has been used in automobile tires for more than 100 years. Today, carbon black is found in computer printer ink and photocopier ink, and also in fumes from burning diesel and other fuels. In April 2011, researchers reported that carbon black nanoparticles can pose a serious threat when inhaled into the lungs [7]. In addition to inflaming the lungs – which most foreign particles do when inhaled – carbon black particles did not kill lung cells via traditional apoptosis (cell death), but rather caused the cells to explode. This kind of cell death where the cells burst apart is known as pyroptosis. The study showed that instead of shrinking on death, the affected lung cells burst open and released their contents, which increased the inflammation, thus producing a secondary effect that makes this contamination especially serious. Martha Monick, professor of Internal Medicine, was the lead author of the study, which was conducted by a team at the University of Iowa's Roy J. and Lucille Carver College of Medicine. The researchers also noted that the concentrations of carbon black used in the study were much higher than the levels to which most people are typically exposed. They noted that these effects would not be expected from simply walking through an area where diesel fumes are present. As in many of these early research studies, the effect on mice and humans could be different, and it is difficult to determine the amount of exposure needed to replicate these effects in humans.

Titanium Dioxide Nanoparticles

Titanium dioxide (TiO2) nanoparticles are used in skin creams and sunscreens as well as paint, toothpaste, food colors, nutritional supplements, and other products. TiO2 nanoparticles have been considered harmless because they do not produce a chemical reaction in the body. However, a study at UCLA's Jonsson Comprehensive Cancer Center found that TiO2 nanoparticles had the potential to cause single- and double-stranded DNA breaks, chromosomal damage, and inflammation in mice. The mice were exposed to TiO2 particles in their drinking water and began showing genetic damage on the fifth day. Robert Schiestl, the study's senior author, said the UCLA study is the first to show this effect from titanium dioxide. The problem, according to the study, is that the TiO2 nanoparticles can concentrate in various organs where they can sever DNA and interfere with cellular systems [8]. In another study reported in 2011, a group of Korean researchers found that TiO2 nanoparticles may inhibit the immune system in mice [9]. These early studies are limited in scope, use higher than normal doses, and do not confirm the extent to which particles may reach certain organs, since the body has various barriers that prevent particles from reaching many organs. This research does not confirm that titanium dioxide poses a health hazard to humans, but it is an early warning signal that suggests further investigation.

Carbon Nanotubes

One of the statistics mentioned in this book is the “world's largest carbon nanotube,” which was a technical goal scientists were working on a few years ago. In the industrial world, many forms of nanotubes are used, including long, short, multiwalled, and so on.

Most types of carbon nanotubes, and other types of nanotubes, have had no safety or toxicology issues. In contrast, short and curling nanotubes appear to present minimal or no hazard, since they are typically removed by macrophages. However, several research studies have shown that the needle-like shape of long carbon nanotubes presents a potential health hazard. A seminal study published in Nature Nanotechnology in 20081) determined that long, thin multiwalled carbon nanotubes behave like asbestos fibers [10]. Asbestos is a proven cause of mesothelioma (cancer of the lining of the lungs).

Current research suggests that care needs to be taken in the handling and use of long carbon nanotubes. The potential dangers posed by long carbon nanotubes require special handling. Many manufacturers who produce and/or use long carbon nanotubes are embedding them in a matrix or substrate that holds them fast and prevents them from separating or flaking off.

For this reason, manufacturers of materials that include long nanotubes embed the CNTs in a liquid or a hard matrix or substrate that prevents the tubes from flaking off. Also, carbon nanotubes can require special handling to minimize health risks to workers. This has given rise to an “intermediaries” sector that produces and/or does the initial processing of CNTs used in industrial or consumer products. Fortunately, high-quality filters used in face masks and ventilation systems can trap most nanoparticles. The airflow and shape of the nanotubes force them against the fibers in the filter, trapping most of them. The current thinking is that carbon nanotubes require special handling, and products that incorporate CNTs need to be evaluated with regard to the full product life cycle, including disposal, of the product.

In April 2013, the National Institute for Occupational Safety and Health (NIOSH) published Current Intelligence Bulletin that reports on occupational exposure to carbon nanotubes and nanofibers. A careful review of 54 animal studies revealed that carbon nanotubes and nanofibers can cause a variety of pulmonary problems, including inflammation, granulomas, and pulmonary fibrosis. These studies were deemed relevant to human health risks because effects observed in animals had also been observed in workers who inhaled particulates of other materials in “dusty jobs.” CNTs were also found to have “similar or greater potency” to other fibers such as silica, asbestos, and ultrafine carbon black. The report estimated the risk of developing early-stage (slight or mild) lung effects over a working lifetime from 0.5 to 16%.

In addition to controlling exposures before recommended exposure levels, the report gave the following advice: “…it is prudent for employers to institute medical surveillance and screening programs for workers who are exposed to CNT and CNF for the purpose of possibly detecting early signs of adverse pulmonary effects including fibrosis.”

It's important to note that these guidelines resulted from animal studies and authors were careful to note that “to date, NIOSH is not aware of any reports of adverse health effects in workers producing or using CNT or CNF.” As recently as 2009, NIOSH had concluded that there was insufficient evidence to recommend medical tests for workers exposed to these engineered nanoparticles; however, the 2013 report reversed this view and indicated that this evidence now exists. This is indicative of how young the field of nanotoxicology is, and suggests that more evidence and safety recommendations – especially in the workplace – will be forthcoming in the coming decade.

Metallic Nanoparticles

Most nanoparticles are composed of common elements such as carbon or iron, or gold, and these elements in larger forms are routinely processed safely by the human body. In terms of delivery, metallic nanoparticles can be absorbed through the skin, breathed in, or consumed in food. They can move across membranes in the body designed to protect organs and are small enough to enter individual cells. Nanostructures can also sever DNA strands that can potentially cause cancer.

The “ecotoxicity” of nanoscale metals and metal oxide particles has been studied to determine whether nanoparticles are toxic, based on a variety of parameters including size, shape, surface charge, composition, degree of aggregation or dispersion, and associated contaminants. The most frequently studied metals are titanium dioxide, zinc oxide, and silver.

Silver, which has been extensively studied, is a well-known germicide. Silver nanoparticles are used in coatings on work surfaces in hospitals and clinics, because of their antibacterial/antiseptic properties. Ionic silver is impregnated in bandages, to treat wounds, and in other applications. Ionic silver (silver atoms with an electron removed) is also used in appliances such as washing machines, most notably in Samsung's “Silver Nano” appliances. Nanoscale silver is also used as an antimicrobial agent in toilet seats, in ice cube machines, food packaging, socks, and other clothing.

Most researchers agree that silver, gold, and other metallic nanoparticles are not especially toxic to humans or other mammals, although silver nanoparticles have been found to be toxic to fish and other aquatic creatures including beneficial microbes. Research studies have shown that silver nanoparticles can accumulate in drainage, sewage, and wastewater, presenting hazards to aquatic creatures and insects. This can seriously disrupt fragile aquatic ecosystems. The antibacterial effect of silver nanoparticles including ionized silver can kill beneficial bacteria that are needed to break down sewage sludge, and this can interfere with biological treatment systems. Silver nanoparticles that wash down drains and enter aquifers are not removed by sewage treatment systems and can persist in the environment. Most silver eventually degrades to a harmless form in the environment. A key question is how long do reactive forms persist before they become harmless, and what adverse effects might occur?

Ongoing research at Duke University has focused on bioaccumulation of nano silver particles in miniature ecosystems (mesosystems). In 2009, the researchers found that nano-silver can form new chemical compounds that are absorbed by plants, insects, and fish; these can also be passed from parent fish to embryos and can disrupt essential bacteria in aquifers and soils. In March 2013, Duke University researchers reported that even low concentrations of silver nanoparticles can cause significant disruptions to natural ecosystems [11].

Silver nanoparticles can also affect fish and other aquatic creatures. A classical 2009 study of zebrafish at the University of Wisconsin-Madison found that embryos exposed to high doses of silver nanoparticles in the laboratory developed serious malformations and congestive heart failure [12]. Studies that exposed adult trout and juvenile carp to silver nanoparticles over a period of days revealed an accumulation of silver particles in the gills and liver, but not mortality – although longer exposures and larger concentrations could have more serious effects.

Researchers have been studying metallic nanoparticles to measure and confirm whether toxicity results in laboratory tests resulted from the size and structure of the particles, the accumulation and concentration levels, and/or the gradual release of ionic silver. One concern is that silver and other metallic nanoparticles could bioaccumulate silently without being detected in aquifers and other ecosystems. These particles may not kill adult fish, but could have a devastating effect on embryos and reproduction of the species. This is what happened with the pesticide DDT – which worked its way from crops into insects and fish, and were absorbed into the eggs of birds, causing some birds to become endangered. DDT was banned in the United States in 1972 and in most (but not all) countries by 2004 under the Stockholm Convention on Persistent Organic Pollutants.

The lingering concern is that an undetected metallic nanoparticle, especially something as well known and “friendly” as silver, could accumulate in an ecosystem over time and cause environmental damage.

12.3 The Regulatory Climate and Safety Knowledge Gaps

Since the 1990s, the nanotech sector has benefited from an accommodating regulatory climate, a kind of regulatory honeymoon. The general feeling was that if something was safe and in use for many years or decades, it was probably safe if nanosized.

There was justification for early confidence in the safety of nanoparticles, since nanoparticles had been in use in some industries for >100 years. Carbon black is a nanopowder used in automobile and rubber products. Materials made of carbon fibers had been in use for years. Cosmetics used nanoparticles in their skin creams and lotions. Some paints and coatings contain nanoparticles.

A decade ago, some companies called their nanoparticle products “micro.” For example, an ingredient listed as “micronized titanium dioxide” in cosmetic creams was actually a nanosized version of titanium dioxide that was ∼40 nm in size. Despite early concerns that the small-sized particles could be photoreactive and generate free radicals, the FDA reviewed the available information and determined that nanoparticles of titanium dioxide were not a new ingredient, but a specific grade of the original product.

In the workplace, manufacturers had in place procedures for handling and processing fine powders and aerosols that were larger in size than nanoparticles and these procedures have been mostly deemed adequate for handling nanomaterials. Given the ability of nanoparticles to slip through even the tiniest pores, there was some concern that standard air filters, even high-tech filters, might not be sufficient to screen nanoparticles in face masks and ventilation systems. However, there is research that shows that nanoparticles even in the range of 4–20 nm get trapped in fine filters because the airflow pushes the particles against the matrix of fibers in the filter and traps them there. Still, the example of the Chinese women who died in the paint factory confirms that any workplace where aerosols, powders, and particulates are present needs to be properly ventilated. Workers need to be protected by the best available wearable filters.

Regulation and oversight of nanotechnology has been a weak link in the nanoinnovation process, not intentionally, but because so little was known about the risk factors involved in producing, handling, transporting, and commercializing nanoparticles. In the mid-2000s, the field of nanotoxicology emerged as a discipline. This gave scientists a foundation for their research and helped enable the global community to intensify its nanosafety activities. Europe and the United States in particular developed a much more focused and integrated effort to conceptualize, map, organize, and conduct meaningful research to determine specific risk factors. Several initiatives were launched to create nanoparticle repositories that could be accessed by the international research community. Guidance was provided by government agencies on safe handling and disposal of nanomaterials. Case studies were conducted. Processes were put in place to evaluate nanotech risks and safety issues.

Conceptualizing Nanosafety

Some of the best visual diagrams portraying expert-hypothesized relationships between risk factors in nanotechnology were developed in 2005 by Kara Morgan. Dr. Morgan did this work as a Senior Advisor for Risk Analysis at the FDA [13]. The diagrams she developed provide a valuable starting point for assessing the safety risks of nanoparticles. These diagrams were developed from a series of conferences, workshops, and interviews with experts using the mental modeling approach that helped identify the individual factors and relationships. Dr. Morgan presented these diagrams as preliminary frameworks for risk analysis of nanoparticles because they did not include data. These diagrams showed how influence diagrams can be designed to show these types of relationships. They provide good templates and examples of how to conceptualize nanotechnology safety factors for any organization that is conducting a nano-safety assessment. The expert-hypothesized relationships represented by the arrows also provided topics for potential research.

Influence diagrams are used to visually portray the relationships between various factors that influence each other, in a system. For example, this framework could be used to assess the risks from carbon nanotubes embedded in a bullet-proof vest, or silver ions released into a stream. Cause and effect relationships are shown by drawing arrows between the elements. The assessment process starts with an overview diagram (see Figure 12.1) that includes a description of the product and how nanomaterials are involved. The next step is to assess the presence of nanomaterials, uptake capacity, transport and fate, and toxic effects – to determine the exposure risks and toxicity. The last step is to evaluate the human health and ecological risks. As Dr. Morgan explained, these factors and relationships are not static. These relationships can change over time, which is why the “time” dimension is shown on the diagram.

Figure 12.1 This influence diagram developed by Dr. Kara Morgan at the FDA shows the expert-hypothesized high-level relationships between a product containing nanomaterials and/or nanoparticles and human and ecological risks (used with permission from Ref. [13]).

These diagrams can be layered or reconfigured to drill down to more detailed analysis, or used to describe hypotheses. For example, the accompanying toxic effects diagram (Figure 12.2) depicts a hypothetical set of relationships that could lead to health effects based on chemical composition, surface coating, surface reactivity, particle size distribution, and adsorption tendency. Linkages can include potential health effects such as inflammation, and genetic or toxic effects in various organs and tissues. Note that these are conceptual and preliminary diagrams to provide an idea how these frameworks can be developed as part of the safety assessment process.

Figure 12.2 This influence diagram shows a set of potential relationships between a product containing nanoparticles and human health risks. It is a mapping tool for conceptualizing nanosafety risks (used with permission from Ref. [13]).

Another important part of safety assessment involves how to dispose of contaminants that may be released (and need to be remediated) when a product such as a cell phone reaches the end of its useful lifespan. Detection and screening of nanomaterials for harmful properties were discussed in a 2013 article [14]. The authors included researchers from Denmark, Norway, and the United States, including Steffen Foss Hansen, Kare Nolde Nielsen, Nina Knudsen, Khara D. Griegerd, and Anders Baun.

In their article, they cited a study by the UK Royal Commission on Environmental Pollution that identified four types of “novel materials” that need to be monitored for environmental impact.

  1. New materials hitherto unused or rarely used on an industrial scale.
  2. New forms of existing materials with characteristics that differ significantly from familiar or naturally occurring forms (e.g., silver and gold).
  3. New applications for existing materials or existing technological products formulated in a new way (e.g., cerium oxide) used as a fuel additive.
  4. New pathways and destinations for familiar materials that may enter the environment in forms different from their manufacture and envisaged use.

This taxonomy provides a good framework for categorizing the various types of nanoinnovations that are emerging today. The researchers also discussed five early warning signs that are useful in assessing environmental risks for new technologies and applications: novelty, persistency, whether the material is readily dispersed, whether it bioaccumulates, and whether its use leads to potentially irreversible action. These are useful frameworks, especially since there is still a lot that we really don't know about nanosafety.

A Shift in Nanotechnology Safety Regulations and Policies

In recent years, regulatory agencies have increased their scrutiny of consumer and industrial products using nanoparticles. Some countries have created repositories and inventories of the most commonly used nanoparticles to facilitate risk assessment. Workplace guidelines on safe handling of nanomaterials are being published by the NNI and other agencies.

While the United States took the early lead in development of innovative nanotechnologies, the European Community has exhibited strong leadership in monitoring and tracking nanosafety. The EU has a variety of very pragmatic programs and initiatives designed to ensure that nanosafety issues are included in the nanoinnovation process.

In Europe, nanomaterials are regulated by the European Chemicals Agency as a “chemical substance” under a regulation called REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals). Nanomaterials that may be hazardous are covered by Regulation 1272, which defines the classification, labeling and packaging (CLP) of substances and mixtures. Additional documents have been published to provide more detailed guidance on handling “nanoform” substances, especially those that are considered hazardous. To provide samples of nanomaterials for testing and evaluation, the Joint Research Centre of the Institute for Health and Consumer Protection created a repository of representative nanomaterials in 2011 (Figure 12.3). A database and information platform called NANOhub hosts several data collections and is designed to consolidate information on nanomaterials that is relevant for safety and risk assessment. A 2012 compendium report [15] describes more than 30 multinational nanosafety projects.

Figure 12.3 In Europe, the Joint Research Centre's nanomaterials repository has created an inventory of nanomaterials. The JRC has provided several thousand vials of nanomaterials to laboratories in France, Germany, the United Kingdom, Belgium, the Netherlands, Denmark, Spain, Poland, Italy, Austria, Slovakia, the United States, Canada, Japan, Korea, China, and Russia (image courtesy of the JRC).

In December 2012, the Danish Consumer Council and Danish Ecological Council, in cooperation with the Technical University of Denmark, established the first nanotechnology database of more than 1200 products that contain or are claimed to be “nano” products. A safety scale is used to rate each product. This database provides a starting point for identifying nanomaterials and ingredients that are potentially hazardous – not only for everyday use in products but also for workers who need to handle carbon nanotubes, chemical liquids or sprays, pesticides, coatings, and other nanomaterials. This rating system also provides a de facto incentive for nanoinnovators to make their products as safe as possible so that they can achieve a “green” rating that indicates low risk.

In the United States, a dozen government agencies fund research on nanotechnology and most of these agencies provide regulatory oversight. The agency responsible for workplace safety is the NIOSH. In early 2013, NIOSH recommended minimizing worker exposure to nanomaterials. The agency recommended that occupational exposures to carbon nanotubes and nanofibers be controlled to reduce worker's potential risk to prevent work-related lung effects. NIOSH was the first US federal agency to issue recommended exposure levels for nanomaterials. In a 2013 Current Intelligence Bulletin, NIOSH reported the results of research showing that various types of carbon nanotubes/carbon nanofibers can cause pulmonary fibrosis, inflammatory effects, and granulomas in laboratory animals exposed by inhalation. NIOSH considers these animal study findings to be relevant to human health risk based on similar lung effects observed in workers exposed to respirable particulates of other materials in dusty jobs.

While enforceable laws governing the use of nanoparticles are still very rare, there are early signs that the regulatory mood is shifting toward stronger safety policies. A notable example is the FDA's 2012 Draft Guidance, which requires companies to conduct additional safety tests and document the safety of nanoparticles used in food, food packaging, food additives, and other food-contact applications. The FDA suggests that companies conduct safety tests for nanoparticles and submit documented safety records. This is a departure from the previous approach that recognized food-related nanoparticles as “generally recognized as safe.” It is becoming increasingly likely that at some point in the future, there will be tighter regulations governing the use, reporting, and labeling of nanoparticles used in foods, cosmetics, and other consumer products.

Labeling Nano

As previously indicated, nanomaterials have not faced the same labeling issues that hindered the adoption in Europe of food products from genetically modified crops. Without a major public incident or nano-related crisis, nanoinnovations have been able to move fairly smoothly into consumer products and industrial processes. The first mandatory labeling of nanotechnology products – for cosmetic products – was enacted in November 2009 by the Council of the European Union and took effect in July 2013. The European Union mandated that the designation [nano] has to be included on the label of any cosmetics that use nanomaterials. The labels are required not as a warning or to alert consumers, but rather to enhance market surveillance by member states. Despite hints or threats to expand nano labeling requirements, the widespread use of special labeling on packages for nanoparticles and nanomaterials has been very slow to develop.

12.4 Perspectives of Nano-Insiders

While interviewing nano-insiders for this book, many of the interviewees expressed insightful opinions on nanosafety issues. A few of the most interesting comments are included here to provide additional perspectives on this very important aspect of nanoinnovation.

Mark Banash (NanoComp): “One of the smartest things the nanocommunity did to allay public fears was to conduct research on safety issues such as absorption of nanoparticles, possible carcinogenic effects, and impact on the environment. A number of studies suggest nanotubes may pose an inhalation hazard and this is correlated to length. Tubes 20 to 50 microns long may be respirable and resemble asbestos type fibers. However, [at Nanocomp] we have shredded, punctured, twisted, pulled, snapped and ground them up into little balls and sat there with some of the most technological advanced air sampling instruments for air contaminants and we've found that nothing comes off of our materials. With our tubes, we don't see contaminants coming off of our products, primarily because our tubes are in the millimeter range, about 700 microns.”

Youseph Yazdi (Johns Hopkins University): “Nanoparticles are ubiquitous in the natural environment. When something is burned or pulverized, you have a natural distribution of particles from large particles to micron and nano-size. In the atmosphere, there are probably nanomaterials that we're breathing all the time – fine nanoparticle soot that firefighters breathe, for instance. Now with modern nanotechnology we can start identifying, filtering, assessing and measuring them in the body. We can identify the accumulation of nanoparticles in various organs.

In the past, there was no way to find out what the size range was or what the effect might be. What's really new in terms of safety is not the existence of nanoparticles. What's new is our ability to understand, measure and manipulate things at the nanoscale. This will help make us safer when exposed to nanoparticles that naturally occur in the environment as well as engineered nanoparticles.”

Fred Klaessig, Ph.D. (Pennsylvania BioNano): “We can learn from history. We are using today's methods to evaluate tomorrow's technologies. For example, Dr. Barnes introduced Argyrol, a nano-silver drug, in 1902 and epidemiology testing was done in 1934. They found that silver develops in the body like silver used in photographic paper and film. Silver turns exposed skin bluish-grey. So the method used to determine the safety of silver was the ‘blueness test.’ If the silver was present in sufficient quantities to turn a person blue, it was deemed unsafe. This is a safety factor using a cosmetic ‘test.’ Some things that were determined safe based on standards used in the past may yet be confirmed safe using modern technologies for testing nanotoxicity.

Fortunately, many commercial nanomaterials are dissolved by stomach acid or removed by white blood cells, which minimizes the health impact. Still, there is no established testing standard for nanoscale solids for a variety of reasons. Regulatory agencies have been reluctant to identify ingredients based on size. The boundary of 100 nanometers defining ‘nanoscale’ is arbitrary. A 90 day inhalation study can cost a million dollars. These are some of the ‘in the trenches’ issues that are still being worked through. We're making progress but much more needs to be done to address future new compositions.”

Patrick Ennis, Ph.D. (Intellectual Ventures): “People are running around worrying about whether a nanoparticle is going to give you a disease. People are worrying about a one in a hundred trillion risk. I gave a presentation where I held up a glass of water and said, this glass is more dangerous than anything we have in nanotechnology. It's been around for thousands of years. Think how many ways it can hurt me. I can fill it up with poison. I can break it in half, cut my foot and die from the infection. I could grind it up into glass powder and put it in the air conditioning system and breathe it – that's not good for us, either. Asbestos, if it gets in your lungs, can give you lung cancer – but if you seal it up and use it properly it has useful functions. Anything is dangerous depending how you use it and how you deploy it.”

Duncan Griffiths (Nanosight): “The nanocommunity has been very conscious up front of the potential for damage on the environment or on living beings, and very proactive in studying these risks. From the beginning there have been studies on these risks, but it is difficult – we're having to come up with completely new measurement methods, and health and safety rules for nanoparticles. For example, you can't just run things through a filter because nanoparticles flow through the pores in the filter. How do we test for nanotoxins in our bodies or in the environment? What if some effects come from individual particles, while others may come from aggregations or certain concentrations?”



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