ISIS Report 10/03/10

Nanotoxicity in Regulatory Vacuum

A vast and rapidly expanding array of engineered nano-products floods the consumer market unregulated as evidence of toxicities accumulate Dr. Mae-Wan Ho

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First cases of nanotoxicity occupational exposure

Seven young women (aged 18–47yrs) working in a paint factory and exposed to nanoparticles for 5–13months fell ill and were admitted to hospital. Two subsequently died. Pathological examinations of the patients' lung tissue showed nonspecific inflammation, fibrosis and foreign-body granulomas (tumours resulting from inflammation) of the pleura (membrane around the lungs). Transmission electron microscopy revealed nanoparticles of polyacrylate lodged in the cytoplasm and the nucleus of cells and in the chest fluid [1]. The polyacrylate nanoparticles were confirmed in the workplace.

These first suspected cases of nanotoxicity from occupational exposure have heightened concerns over the huge and rapidly expanding array of nanotechnology products in the market that remains unregulated despite accumulating evidence that many nano-ingredients, including those most common in commercial use, are indeed toxic.

Common nano-ingredients are toxic

Nanotechnologies are technologies at the scale of nanometres (10^-9m), where new quantum effects can alter the chemistry and physics of elements and compounds, offering exciting new possibilities in industrial applications, and for exactly the same reasons, posing unprecedented risks to health and the environment.

It was difficult to separate hype from reality when it all began, and almost no one worried about safety [2] (Nanotechnology, a Hard Pill to Swallow, SiS 16). But evidence of health hazards soon started to emerge [3-5] (Nanotox, Metal Nanoshells, Cure or Curse?, Nanotubes Highly Toxic, SiS 21), and nanotoxicology became established as a discipline in 2005 [6] (Nanotoxicity: A New Discipline, SiS 28). By then, many serious health impacts had already been observed in laboratory experiments; and more appeared in subsequent years. I describe a few recent examples below.

In 2009, researchers at University of California Los Angeles Jonsson Cancer Center led by Robert Schiest reported that [7] titanium dioxide nanoparticles (TiO₂), found in “everything from cosmetics and sunscreens to paint and vitamins” (see Box), caused DNA damage when fed to mice. They induced breaks in DNA, damaged chromosomes, and caused inflammation of tissues; “all of which increase the risk of cancers.”

The mice were exposed to the nanoparticles in their drinking water, and genetic damage started showing up on the fifth day [8], equivalent to occupational exposure in humans of 1.6 years. Once taken into the body, the TiO₂ nanoparticles accumulate in different organs because the body cannot eliminate them, and they are so small that they can go everywhere.

These latest findings confirm the results of numerous other studies indicating that nano-TiO₂ increases cell death, DNA damage, and genome instability in the short-term and the risk of cancer in the longer term. A team of researchers at several institutes in Taiwan showed that exposing mammalian cells to TiO₂ nanoparticles at 10 ppm in the short-term (days) resulted in enhancement of cell growth and survival, and increase in reactive oxygen species (oxidative stress). In the long-term – after 12 weeks - a dramatic increase in transformed (cancerous) cells was observed, resulting from a disturbance of cell division and genome instability [9]. Similar toxicities have been found for other nanoparticles often used with TiO₂, such as ZnO₂ and SiO₂ [10, 11].

Nano-silver, even more widely used than nano-TiO₂, is toxic to beneficial bacteria that break down wastes and recycle nutrients in the soil [12]. It also killed half of all zebrafish embryos in laboratory tests at concentrations of 25 to 50 ppm [13]; whereas a solution of ordinary silver ions (Ag⁺) was non-toxic.

Fullerenes, a new form of carbon in the shape of a football (buckyball) discovered in the mid 1980s, rapidly found applications in electronics, electro-optics and much more besides, including cosmetics. They are being considered for drug delivery and cancer therapy. Fullerenes caused oxidative brain damage (through lipid peroxidation) in juvenile largemouth bass after 48 hours of exposure at 0.5 ppm [14], mostly likely through the ability of fullerenes to home in on lipid-rich membrane. One main route to the brain is via the olfactory nerve. Fullerenes were also highly toxic to zebrafish embryos at 0.2 ppm [15]. Carbon nanotubes, long thin structures derived from fullerenes and often compared to asbestos, caused inflammation and granulomas when instilled into the lungs of mice. These results have now been confirmed in a study in which the mice inhaled aerosols of multiwall carbon nanotubes. Inflammation and granulomas were found in the lungs even at the lowest concentration of 0.1 mg/m³ [16].

Quantum dots are nanosized semi-conductors that generate electron-hole pairs confined in all three dimensions (quantum confinement), and hence behave like giant molecules rather than bulk semiconductors [17]. They have numerous applications in light emitting diodes, transistors, solar cells etc., and are also being developed for drug delivery, cancer therapy and cell imaging. Unfortunately, most quantum dots contain highly toxic metals such as cadmium, which tends to be released when the quantum dots enter the cells or organisms. This was thought to be the main reason why CdSe/ZnSe quantum dots at nanomolar (10^-9mol) concentrations were toxic to Daphnia magna, but much less toxic than the equivalent concentration of cadmium ions [18]. However, CdTe quantum dots coated with hydrophilic sodium thioglycolate caused disruption in a cultured monolayer of Caco-2 human intestinal cells and cell-death at 0.1 ppm, which was thought to be caused by the quantum dots, rather than cadmium [19]. In a third study, CdSe/ZnS quantum dots injected intravenously into mice caused marked vascular thrombosis in the lungs at 0.7 to 3.6 nanomol per mouse, especially when the quantum dots had carboxylate surface groups [20]. Three out of four mice injected at the higher concentration died immediately. The injected quantum dots were mainly found in the lungs, liver and blood; and the authors hypothesized that the quantum dots activated the coagulation cascade through contact. In fact, many kinds of nanoparticles enhance the formation of insoluble fibrous protein aggregates (amyloids) [21], which are associated with human diseases including Alzheimer’s, Parkinson’s and Creutzfeld-Jacob disease.

A burgeoning trillion dollar industry with no safeguards in place

There are now more than 1 000 nanotechnology products on the market (see Box), ranging from microelectronics, solar cells, medicine, to cosmetics, clothing, food, and agriculture [22].

Nanotechnology products already on the market

A public inventory currently lists more than 1 000 nanotechnology products on the market [22]; but this is likely to be an underestimate, as both the number and variety are growing rapidly, and some companies may be reluctant to disclose ingredients produced by nanotechnology.

The most numerous products contain nanosilver particles used as an antibacterial in filters for air conditioners, coating for refrigerators, food packaging, tableware, kitchenware, mobile phones, baby toys, pacifiers, cups and mugs, toothpaste, pet products, clothing, bath and sporting towels, sprays, and food supplement.

Also common are titanium oxide and zinc oxide nanoparticles used in cosmetics and sunscreens. Titanium oxide and silicon oxide nanocrystals are combined with organic polymers in anti-dirt, anti-graffiti coatings [23, 24] on windscreens and other surfaces.

Carbon nanotubes and nanofibres are incorporated in sports goods such as tennis rackets, racing bicycle frames and golf club to give strength at reduced weight [22]. They are widely used as conductive elements in computer microprocessors, flash memory, organic light emission diodes, and light emission diodes for display screens, giving high performance at reduced size and power consumption. Carbon nanotubes are in heavy-duty anti-corrosion coatings for sea-going vessels [25].

Semi-conducting quantum dots have found applications in laser diodes, LEDs for a new kind of display screen, as well as solar panels, and batteries.

The food and cosmetic industry have taken nanotechnology to heart, in addition to the nanosilver used in packaging and appliances. A new line of nutritional and skincare supplements called Nanoceuticals^TM includes cocoa nanoclusters to enhance flavour [22]. Nanosized liposomes are used for more efficient nutrient delivery and other “nanostructured supplements”; nanosized self-assembled structured liquids (e.g., Canola Active Oil) are sold as anti-cholesterol. Nanostarch adhesive for McDonald’s burger containers is saving cost and energy. Nanoclay mixed with plastic in beer bottles makes them stronger and less permeable to gas. Nanoparticles/nanospheres-encapsulated vitamins and oils are also on offer.

At the farm, fertilizers and pesticides are dispensed with nanoclay particles and other materials for slow release and increased potency [12]

The UK government is about to announce a new strategy for nanotechnologies [26], predicted by the US National Science Foundation to worth more than $1 trillion by 2015 [27].

The European Union’s Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) report in 2006 [28] admitted that existing toxicological and ecotoxicological methods may not be sufficient to address the risks of nanoparticles. Exposure to nanoparticles having characteristics not previously encountered in evolution (and in increasing concentrations and varieties) may well challenge the normal defence mechanisms associated with the immune and inflammatory systems. In particular, safety evaluation of nanoparticles and nanostructures cannot rely on the toxicological and ecotoxicological profile of the bulk material that has been historically determined.

A report released in 2009 by the European Commission Joint Research Centre’s Institute for Health and Consumer [29] called for “further development of thorough characterisation.”

The US Environment Protection Agency (EPA) officials are planning to take enforcement action against companies manufacturing or importing carbon nanotubes that have not submitted premanufacture notices (PMNs) as required by its Toxic Substance Control Act (TSCA) [30]. EPA may issue additional test rules for carbon nanotubes. Otherwise, EPA has been criticised for its “no-data, no risk” approach [12].

The European guidelines for nanotechnology fall under the Registration, Evaluation, Authorisation and Restriction of Chemical Substances (REACH), intended to take a “no data, no market” approach, requiring companies to provide evidence of the safety of their chemicals before they can enter the marketplace. In practice, however, REACH fails to apply a robust precautionary principle [12]. As it was designed to regulate chemicals produced in quantities of one tonne or more, manufacturers and handlers of nanomaterials could simply limit the scale of their operations to escape regulation. REACH is also weakened by the exclusions from regulatory purview of some materials that were previously shown to be safe in larger particle sizes, such as TiO₂.

In 2008, the European Commission, removed carbon and graphite from its exclusion

list, noting that at the nano-scale, these materials have not demonstrated themselves to be risk-free. The European Food Safety Authority (EFSA) has questioned the adequacy of established toxicological methodologies for testing nanomaterials. But a high-ranking official at the European Commission’s Health and Consumer Affairs Directorate General (DG SANCO), Robert Madelin, when asked whether supermarket foods, possibly containing nanotechnology, were safe for consumers, he answer emphatically that they were; and scolded consumer groups and non-government organizations for attacking nanotechnology [12].

In early 2009, the European Commission adopted a proposal that would allow the EU to regulate nano-foods under the Novel Foods Regulation. The European Parliament has endorsed the proposal, further asking the Commission to include mandatory nanomaterial labels in the list of ingredients. No further action has yet been taken.

Nano-products have been foisted on unsuspecting consumers essentially in a regulatory vacuum, while billions of taxpayer’s money are being spent on research and development. To compound the risks, there is no standard protocol for the manufacture of any product, let alone standards of characterisation of the products. Some of these problems are only beginning to be addressed by the Organisation for Economic Cooperation and Development [31].

The Royal Society and the Royal Academy of Engineering, two of the UK’s most prestigious scientific societies produced the first report in 2004 [32] highlighting both the risks and the opportunities of nanotechnologies. However, there has been a distinct lack of progress in addressing the risks; UK still does not have a dedicated centre for risk research in nanomaterials [33].

Nanoparticles, natural, artificial, old and new

What’s new about nanoparticles, as far as risk is concerned, is that many of them are chemically inert as ordinary ions or as larger particles (and hence never had to go through regulatory approval before the nanoparticles were used); but as soon as the particle size reaches nanometre dimensions, they acquire novel physicochemical properties, causing oxidative stress and breaking DNA, and they can get access to every part of the body including the brain, via inhalation and the olfactory nerve.

A comprehensive review [34] by Cristina Buzea and colleagues at Queen’s University, Kingston, Ontario, in Canada, pointed out that human beings have been exposed to natural nanoparticles since the origin of our species, in the form of viruses, dusts from terrestrial and extraterrestrial dust storms, volcanic eruptions, forest fires, and sea salt aerosols (which are largely beneficial).

Nanoparticles have been created by human activities for thousands of years, by burning wood in cooking, and more recently, chemical manufacturing, welding, ore refining and smelting, burning of petrol in vehicles and airplane engines, burning sewage sludge, coal and fuel oil for power generation, all of which are already known to have health impacts. Automobile exhaust particular pollution is linked to heart and lung diseases and childhood cancers.

Tobacco smoke is composed of nanoparticles with size ranging from around 10 nm up to 700 nm, with a peak around 150 nm. It has a very complex composition with more than 100 000 chemical components and compounds. First or second hand cigarette smoke is associated with an increased risk of chronic respiratory illness, lung cancer, nasal cancer, and cardiovascular disease, as well as other malignant tumours, such as pancreatic cancer, and genetic alterations. Children exposed to cigarette smoke show an increased risk of sudden infant death syndrome, middle ear disease, lower respiratory tract illnesses, and exacerbated asthma.

Dust from building demolition is an important source of particulate pollution. Older buildings are likely to contain asbestos, fibres, lead, glass, wood, paper and other toxic particles

Natural and artificial nanoparticles overlap. For example, C60 fullerenes have been reported in 10 000-year-old ice core samples [35].

It is important to distinguish nanoparticles from nano-structured materials that do not exist as free particles during any part of the manufacturing process, which therefore are not expected to present the same hazards.

Nevertheless we are faced with an unprecedented and ever-growing volume and diversity of nanoparticles as nanotechnologies take off in all directions.

Diseases associated with nanoparticles

Nanoparticles may be inhaled, ingested or taken in through contact with the skin. The known possible adverse health impacts are summarised in Figure 1 [34], which includes both natural and anthropogenic nanoparticles. Obviously not all nanoparticles are harmful, but without exhaustive tests especially in the case of the newly engineered nanoparticles, it is impossible to tell.

Figure 1 Diseases linked to nanoparticles from different pathways of exposure [34]

Diseases associated with inhaled nanoparticles include asthma, bronchitis, emphysema, lung cancer, and neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases. Nanoparticles in the gastrointestinal tract have been linked to Crohn’s disease and colon cancer. Nanoparticles that enter the circulatory system are implicated

in arteriosclerosis, blood clots, arrhythmia, heart diseases, and ultimately death from heart disease. Nanoparticles entering other organs, such as liver, spleen, etc., may lead to diseases of these organs. Some nanoparticles are associated with autoimmune diseases, such as systemic lupus erythematosus, scleroderma, and rheumatoid arthritis.

Conclusion

There is clearly an urgent need not only to stem but also to reverse the unregulated tide of nanoparticles that are released onto the market. In view of the existing evidence, the following actions should be taken.

· Engineered nano-ingredients in food, cosmetics and baby products for which toxicity data already exist (e.g., silver, titanium oxide, fullerenes, etc.) should be withdrawn immediately

· A moratorium should be imposed on the commercialization of nano-products until they are demonstrated safe

· All consumer products containing nanotechnology should be clearly labelled

· The Health and Consumer Protection Directorate General (SANCO) of the European Commission should require manufacturers of nano-products to register their products in a database that is publicly available on the SANCO website [12]

· The voluntary code of conduct for nanotechnology research that the European Commission adopted in 2008 should become mandatory [12]: Nanotechnology research activities must be made comprehensible to the public, performed in a transparent manner, accountable, safe and sustainable, and not pose a threat to the environment

· A robust regulatory programme on nanotechnology - including characterisation and standardisation of manufacture - should be implemented as soon as possible

· There should be earmarked funding for research into the hazards of nanotechnology.

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