Sarah Belfield - Reporter and writer, freelance

s a r a h b e l f i e l d

reporter & writer, freelance

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TINY PARTICLES: BIG RISKS

(Australasian Science, October 2005)

Scientists face a long journey on the road to answering consumer and occupational health and safety questions surrounding the emerging field of nanotechnology. Sarah Belfield reports.

MUCH remains unknown about the health effects of some nanotechnology products. With nano-products already on the retail market — including stain-resistant clothes, transparent sunscreens and moisturisers containing nano-sized spheres — commercial progress is arguably outpacing medical knowledge at this point.

But the greatest unknown right now is the community reaction to this mismatch between manufacturing know-how and medical know-not. Will we soon witness a global turning away from nanotechnology like the high-profile rejection of genetically modified foods?

A November 2004 government survey found that only 1-2% of people saw benefits or had concerns about nanotechnology. Even so, 49% of people wished to be consulted about developments in nanotechnology.

The issue is now drawing attention from authorities, with an inquiry into workplace exposure to toxic dust being undertaken by the Senate Community Affairs References Committee. One of seven points being investigated is "the potential of emerging technologies, including nanoparticles, to result in workplace-related harm". Three public hearings were scheduled for September and October, and the committee will report by 1 December this year.

Awakening interest

Nanotechnology is expected to mushroom in the decade ahead. This time last year, US nanotechnology firm Lux Research projected that sales of products incorporating nanotechnology will be worth US$2.6 trillion globally in 2014, which will be 10 times more than projected biotechnology revenues.

According to an independent working group on nanotechnology for the Australian Prime Minister's Science, Engineering and Innovation Council (PMSEIC), global annual spending by governments on nanotechnology more than quadrupled from US$1 billion to about US$4.5 billion between 2000 and 2004.

Australia has been a small fish in the big pond of nanotechnology. The PMSEIC working group said that by 2003 Australia was investing roughly up to A$100 million per year in nanotechnology, with at least half coming from government sources.

Australia has more than 50 nano-focused companies, according to a report published this year by Invest Australia. The companies are producing or developing components such as nanotubes, nanopowders, nanoscale latex, nanofibres, thin films, nanowires, nanodots, spray-on surface treatments, biofibres, magnetic biobeads, ceramic particles and dendrimers.

While engineered nanomaterials are only just emerging, many kinds of nanoparticles have been around for decades, centuries or longer. These incidental nanoparticles — also called ultrafine particles — are produced in fire smoke, auto and diesel exhaust, and by smelting and welding.

When asked in July whether the Senate committee will have scope to consider these incidental nanoparticles, Senator Lyn Allison (a committee member) said it will consider all the evidence brought to it by way of submission unless it is clearly outside the terms of reference.

In its submission to the Senate inquiry, lobby group Friends of the Earth estimated that more than 300,000 Australian workers may be exposed to nanoparticles incidentally produced in high-energy industrial processes. It also estimated as many as 700 people were employed in activities where they may be regularly exposed to synthetic nanoparticles in some form. The group said this number was likely to at least double over the next 5 years.

"There is currently no regulatory requirement for nanotechnology researchers or nanoparticle manufacturers to take into account the novel and toxic properties of nano-sized materials, or to protect their workers from exposure," the group said.

"Products containing synthetic nanomaterials should be withdrawn from public sale," it said, at the same time calling for a moratorium on the research, development and production of synthetic nanoparticles and other nanomaterials while regulations are being developed.

Australia's regulators seem aware of the challenges nanomaterials may present. According to the PMSEIC working group, Australia's Therapeutic Goods Administration had "committed to following through" on setting up criteria/guidelines for the safe use of nanoparticle technology where it applied to therapeutic goods. A joint submission to the PMSEIC working group by the National Industrial Chemicals Notification and Assessment Scheme and the National Occupational Health and Safety Commission questioned whether the current safety and risk assessment framework can be applied to nanotechnology or whether a new risk assessment paradigm would be needed.

But what power does the Senate committee have to see its eventual findings and recommendations acted upon? "Directly, none," Senator Allison said. "The committee's power comes from the examination of evidence brought to it and the reporting of that evidence in a public forum. The government has an obligation to publicly respond to recommendations made by such inquiries."

Mining company Rio Tinto said it will be taking an interest in the findings and recommendations coming out of the inquiry. Company spokesman Ian Head said Rio Tinto had contributed to submissions made to the inquiry by the Minerals Council of Australia and the Australian Institute of Occupational Hygienists.

Exposure via the lungs

Mining is one industry where incidental nanoparticles from a variety of sources can be found in the workplace. Diesel exhaust is an area of active industry research because of the high levels of fine and ultrafine particles produced. "Of the combustion aerosols in the mining environment, diesel exhaust aerosol is of particular concern because it is almost entirely respirable in size, with more than 90% of the particles, by mass, having an aerodynamic diameter less than 1.0 micrometre," said US-based researchers Bruce Cantrell and Jon Volkwein in the 2001 monograph Aerosol Measurement: Principles, Techniques, and Applications.

Rio Tinto has participated in the Diesel Emissions Evaluation Program, a research consortium aiming to reduce people's exposure to diesel exhaust in underground mining. While some of Rio Tinto's operations produce incidental particles, Head said that the company had measures to control them as much as possible as part of its occupation health and environmental standards. He said the worker protection protocols in place for nanoparticles were similar to protocols for larger particles "but Rio Tinto notes that as yet there are no agreed standards for measuring nanoparticles".

Mining company BHP Billiton declined to respond to invitations extending over 3 weeks to discuss the topic of nanoparticles and nanotechnology.

Dr Vincent Castranova of the US Centers for Disease Control and Prevention (CDC) recently overviewed research findings on the toxicity of incidental nanoparticles during his visit to Australia in July. Castranova is branch chief of pathology and physiology research at the CDC's National Institute for Occupational Safety and Health (NIOSH).

"We know a lot about these incidental particles — diesel exhaust, titanium dioxide in the ultrafine mode," he told delegates at a nanotechnology conference in Perth. "Is that appropriate to nanotechnology-generated particles? We don't know."

To picture the size of an ultrafine particle, imagine dividing 1 mm into one million equal parts. One of those parts is a nanometre. Now imagine gluing 100 of these parts end-to-end. Any particle narrower than this is classified as "ultrafine". The next size category up is "fine" (100 nm to 2.5 micrometres).

Castranova cited animal studies where ultrafine particles were inhaled. One of those studies looked at the inhalation of 8 nm and 26 nm particles, and animals inhaled particles while at rest or while exercising. During rest, 66% of 26 nm particles and 80% of the 8 nm particles were deposited in the lung. Deposition was greater during exercise: 83% for the larger particles and 94% for the smaller particles.

Another study showed that fine particles were removed effectively by alveolar macrophage cells that engulf foreign particles and clear them from the lung. However, the macrophages seemed to have a tough time with ultrafine particles. Castranova said 70-80% of these particles evaded engulfment, probably because the number of these particles is so great.

After evading macrophages, ultrafine particles can move across the lung surface and into the walls of the lung's alveoli in a process called interstitialisation. Castranova cited a study at the University of Rochester in the US where rats inhaled fine or ultrafine titanium dioxide for 12 weeks. On average, 44% of the ultrafine particles inhaled became trapped in the alveolar walls. This occurred with only 13% of the fine particles. More inflammation is observed with trapped ultrafine trapped material. Castranova said that ultrafine material also more strongly inhibits the lung from clearing itself of particles.

Tumours are another measure of toxicity. Castranova cited a study that exposed animals to fine particles of titanium dioxide for 2 years and found that tumours developed once a dose of 250 mg/cu.m was reached. A second study used ultrafine titanium dioxide particles and found tumours at a dose as low as 10 mg/cu.m.

"They saw tumours at a dose where there were no tumours at all with the fine material," Castranova said. "So what I'm saying is regulating ultrafine titanium dioxide as fine titanium dioxide is probably inappropriate. Probably you need a different regulation for the ultrafine material."

Castranova said it was recently shown that inhaled ultrafine particles can be taken up by the sensory neurons in the airways and nasal cavity, providing a route for ultrafine particles to the brain. "Welding fume contains ultrafine manganese, and manganese has been associated [with] Parkinson's disease," he said. "Is the Parkinson's disease with welders associated with the uptake of those ultrafine particles that contain the manganese and the transport of the manganese to the brain? We don't know."

A 2003 NIOSH review paper on the health effects of welding cited a study comparing Parkinson's disease in welders and non-welders. The review's author said the study's conclusion — that Parkinson's in welders was different only in its age of onset — suggested "welding may be a possible risk factor for the development of early onset Parkinson's disease." However, the study's findings could not definitively prove whether manganese was the causative agent, and it was possible different components of the welding fume and other occupational and environmental exposures could be responsible for the neurological changes observed.

Castranova said that ultrafine particles tend to aggregate in the environment. "When they aggregate they're no longer nano — they're more like micro in diameter. The question is: how do they behave in the lung?" He said the lung is lined by a film of a substance called dipalmityl lecithin, and this could break the weak intermolecular forces holding aggregated nanoparticles together.

What happens to particles applied to the skin is another branch to this line of medical research. Castranova said a 1 micrometre particle put on the skin just stays there because the skin is a good barrier. He then presented a NIOSH research paper using 500 nm fluorescent beads. "They put them on the skin and then, by confocal microscopy, looked at the penetration of the beads through the skin," he said. "If they just put them on the skin and left the skin there, the beads didn't move. But if they flexed the skin, the mechanical flexing moved those particles down into the depths of the skin.

"So particles less than 500 nm have the potential to move through the skin," he said. "Because most of our workers are moving... we're going to flex the skin. And so there's potential for those particles to get into the skin."

Engineered nanomaterials

Carbon nanotubes are being developed around the world for possible electronic, aerospace, automotive, computer and clothing applications because of their flexibility, strength and ability to conduct electricity and heat. "Our preliminary data was for single-walled carbon nanotubes," he said. "When we exposed the [animal] lung to them they were not very inflammatory. There was a little bit of inflammation within the first week, but at 60 days it was back down to normal... By using that criteria they would have been called 'benign dust'."

Castranova said the nanotubes that had breached the alveolar walls of the lung were behaving like the lung's basal protein layer. This meant that collagen — the key protein in skin, tendons, bones and connective tissue — formed over the nanotubes to produce abnormal fibrous tissue. He said the collagen formed very rapidly in 7 days and progressed through 60 days after the animals had been exposed to the nanotubes. To the best of his group's knowledge, Castranova said that collagen formation will progress longer if test animals are allowed to live longer.

"We were getting a fairly extensive pulmonary fibrosis, which was unique by the shape and the composition of that material," he said. "What was interesting is we got that without prolonged inflammation. With coal dust and silica you need prolonged inflammation to get fibrosis. These [carbon nanotube] materials are behaving somewhat differently."

When asked what advice would he give industry about staying abreast of health research on nanomaterials, Castranova told conference delegates: "In the United States we have what's called a National Nanotechnology Initiative. NIOSH is part of that initiative, and what we've suggested is not only do you need to fund research and development of products but you need to fund research into potential toxicity so that these products can be used in an appropriate and responsible manner.

"We think if we know enough we can protect the worker and the user. Right now we don't know enough."

s a r a h b e l f i e l d reporter & writer, freelance

About Services Clips Ideas Contact	Sample clip TINY PARTICLES: BIG RISKS (Australasian Science, October 2005) Scientists face a long journey on the road to answering consumer and occupational health and safety questions surrounding the emerging field of nanotechnology. Sarah Belfield* reports.* MUCH remains unknown about the health effects of some nanotechnology products. With nano-products already on the retail market — including stain-resistant clothes, transparent sunscreens and moisturisers containing nano-sized spheres — commercial progress is arguably outpacing medical knowledge at this point. But the greatest unknown right now is the community reaction to this mismatch between manufacturing know-how and medical know-not. Will we soon witness a global turning away from nanotechnology like the high-profile rejection of genetically modified foods? A November 2004 government survey found that only 1-2% of people saw benefits or had concerns about nanotechnology. Even so, 49% of people wished to be consulted about developments in nanotechnology. The issue is now drawing attention from authorities, with an inquiry into workplace exposure to toxic dust being undertaken by the Senate Community Affairs References Committee. One of seven points being investigated is "the potential of emerging technologies, including nanoparticles, to result in workplace-related harm". Three public hearings were scheduled for September and October, and the committee will report by 1 December this year. Awakening interest Nanotechnology is expected to mushroom in the decade ahead. This time last year, US nanotechnology firm Lux Research projected that sales of products incorporating nanotechnology will be worth US$2.6 trillion globally in 2014, which will be 10 times more than projected biotechnology revenues. According to an independent working group on nanotechnology for the Australian Prime Minister's Science, Engineering and Innovation Council (PMSEIC), global annual spending by governments on nanotechnology more than quadrupled from US$1 billion to about US$4.5 billion between 2000 and 2004. Australia has been a small fish in the big pond of nanotechnology. The PMSEIC working group said that by 2003 Australia was investing roughly up to A$100 million per year in nanotechnology, with at least half coming from government sources. Australia has more than 50 nano-focused companies, according to a report published this year by Invest Australia. The companies are producing or developing components such as nanotubes, nanopowders, nanoscale latex, nanofibres, thin films, nanowires, nanodots, spray-on surface treatments, biofibres, magnetic biobeads, ceramic particles and dendrimers. While engineered nanomaterials are only just emerging, many kinds of nanoparticles have been around for decades, centuries or longer. These incidental nanoparticles — also called ultrafine particles — are produced in fire smoke, auto and diesel exhaust, and by smelting and welding. When asked in July whether the Senate committee will have scope to consider these incidental nanoparticles, Senator Lyn Allison (a committee member) said it will consider all the evidence brought to it by way of submission unless it is clearly outside the terms of reference. In its submission to the Senate inquiry, lobby group Friends of the Earth estimated that more than 300,000 Australian workers may be exposed to nanoparticles incidentally produced in high-energy industrial processes. It also estimated as many as 700 people were employed in activities where they may be regularly exposed to synthetic nanoparticles in some form. The group said this number was likely to at least double over the next 5 years. "There is currently no regulatory requirement for nanotechnology researchers or nanoparticle manufacturers to take into account the novel and toxic properties of nano-sized materials, or to protect their workers from exposure," the group said. "Products containing synthetic nanomaterials should be withdrawn from public sale," it said, at the same time calling for a moratorium on the research, development and production of synthetic nanoparticles and other nanomaterials while regulations are being developed. Australia's regulators seem aware of the challenges nanomaterials may present. According to the PMSEIC working group, Australia's Therapeutic Goods Administration had "committed to following through" on setting up criteria/guidelines for the safe use of nanoparticle technology where it applied to therapeutic goods. A joint submission to the PMSEIC working group by the National Industrial Chemicals Notification and Assessment Scheme and the National Occupational Health and Safety Commission questioned whether the current safety and risk assessment framework can be applied to nanotechnology or whether a new risk assessment paradigm would be needed. But what power does the Senate committee have to see its eventual findings and recommendations acted upon? "Directly, none," Senator Allison said. "The committee's power comes from the examination of evidence brought to it and the reporting of that evidence in a public forum. The government has an obligation to publicly respond to recommendations made by such inquiries." Mining company Rio Tinto said it will be taking an interest in the findings and recommendations coming out of the inquiry. Company spokesman Ian Head said Rio Tinto had contributed to submissions made to the inquiry by the Minerals Council of Australia and the Australian Institute of Occupational Hygienists. Exposure via the lungs Mining is one industry where incidental nanoparticles from a variety of sources can be found in the workplace. Diesel exhaust is an area of active industry research because of the high levels of fine and ultrafine particles produced. "Of the combustion aerosols in the mining environment, diesel exhaust aerosol is of particular concern because it is almost entirely respirable in size, with more than 90% of the particles, by mass, having an aerodynamic diameter less than 1.0 micrometre," said US-based researchers Bruce Cantrell and Jon Volkwein in the 2001 monograph Aerosol Measurement: Principles, Techniques, and Applications. Rio Tinto has participated in the Diesel Emissions Evaluation Program, a research consortium aiming to reduce people's exposure to diesel exhaust in underground mining. While some of Rio Tinto's operations produce incidental particles, Head said that the company had measures to control them as much as possible as part of its occupation health and environmental standards. He said the worker protection protocols in place for nanoparticles were similar to protocols for larger particles "but Rio Tinto notes that as yet there are no agreed standards for measuring nanoparticles". Mining company BHP Billiton declined to respond to invitations extending over 3 weeks to discuss the topic of nanoparticles and nanotechnology. Dr Vincent Castranova of the US Centers for Disease Control and Prevention (CDC) recently overviewed research findings on the toxicity of incidental nanoparticles during his visit to Australia in July. Castranova is branch chief of pathology and physiology research at the CDC's National Institute for Occupational Safety and Health (NIOSH). "We know a lot about these incidental particles — diesel exhaust, titanium dioxide in the ultrafine mode," he told delegates at a nanotechnology conference in Perth. "Is that appropriate to nanotechnology-generated particles? We don't know." To picture the size of an ultrafine particle, imagine dividing 1 mm into one million equal parts. One of those parts is a nanometre. Now imagine gluing 100 of these parts end-to-end. Any particle narrower than this is classified as "ultrafine". The next size category up is "fine" (100 nm to 2.5 micrometres). Castranova cited animal studies where ultrafine particles were inhaled. One of those studies looked at the inhalation of 8 nm and 26 nm particles, and animals inhaled particles while at rest or while exercising. During rest, 66% of 26 nm particles and 80% of the 8 nm particles were deposited in the lung. Deposition was greater during exercise: 83% for the larger particles and 94% for the smaller particles. Another study showed that fine particles were removed effectively by alveolar macrophage cells that engulf foreign particles and clear them from the lung. However, the macrophages seemed to have a tough time with ultrafine particles. Castranova said 70-80% of these particles evaded engulfment, probably because the number of these particles is so great. After evading macrophages, ultrafine particles can move across the lung surface and into the walls of the lung's alveoli in a process called interstitialisation. Castranova cited a study at the University of Rochester in the US where rats inhaled fine or ultrafine titanium dioxide for 12 weeks. On average, 44% of the ultrafine particles inhaled became trapped in the alveolar walls. This occurred with only 13% of the fine particles. More inflammation is observed with trapped ultrafine trapped material. Castranova said that ultrafine material also more strongly inhibits the lung from clearing itself of particles. Tumours are another measure of toxicity. Castranova cited a study that exposed animals to fine particles of titanium dioxide for 2 years and found that tumours developed once a dose of 250 mg/cu.m was reached. A second study used ultrafine titanium dioxide particles and found tumours at a dose as low as 10 mg/cu.m. "They saw tumours at a dose where there were no tumours at all with the fine material," Castranova said. "So what I'm saying is regulating ultrafine titanium dioxide as fine titanium dioxide is probably inappropriate. Probably you need a different regulation for the ultrafine material." Castranova said it was recently shown that inhaled ultrafine particles can be taken up by the sensory neurons in the airways and nasal cavity, providing a route for ultrafine particles to the brain. "Welding fume contains ultrafine manganese, and manganese has been associated [with] Parkinson's disease," he said. "Is the Parkinson's disease with welders associated with the uptake of those ultrafine particles that contain the manganese and the transport of the manganese to the brain? We don't know." A 2003 NIOSH review paper on the health effects of welding cited a study comparing Parkinson's disease in welders and non-welders. The review's author said the study's conclusion — that Parkinson's in welders was different only in its age of onset — suggested "welding may be a possible risk factor for the development of early onset Parkinson's disease." However, the study's findings could not definitively prove whether manganese was the causative agent, and it was possible different components of the welding fume and other occupational and environmental exposures could be responsible for the neurological changes observed. Castranova said that ultrafine particles tend to aggregate in the environment. "When they aggregate they're no longer nano — they're more like micro in diameter. The question is: how do they behave in the lung?" He said the lung is lined by a film of a substance called dipalmityl lecithin, and this could break the weak intermolecular forces holding aggregated nanoparticles together. What happens to particles applied to the skin is another branch to this line of medical research. Castranova said a 1 micrometre particle put on the skin just stays there because the skin is a good barrier. He then presented a NIOSH research paper using 500 nm fluorescent beads. "They put them on the skin and then, by confocal microscopy, looked at the penetration of the beads through the skin," he said. "If they just put them on the skin and left the skin there, the beads didn't move. But if they flexed the skin, the mechanical flexing moved those particles down into the depths of the skin. "So particles less than 500 nm have the potential to move through the skin," he said. "Because most of our workers are moving... we're going to flex the skin. And so there's potential for those particles to get into the skin." Engineered nanomaterials Carbon nanotubes are being developed around the world for possible electronic, aerospace, automotive, computer and clothing applications because of their flexibility, strength and ability to conduct electricity and heat. "Our preliminary data was for single-walled carbon nanotubes," he said. "When we exposed the [animal] lung to them they were not very inflammatory. There was a little bit of inflammation within the first week, but at 60 days it was back down to normal... By using that criteria they would have been called 'benign dust'." Castranova said the nanotubes that had breached the alveolar walls of the lung were behaving like the lung's basal protein layer. This meant that collagen — the key protein in skin, tendons, bones and connective tissue — formed over the nanotubes to produce abnormal fibrous tissue. He said the collagen formed very rapidly in 7 days and progressed through 60 days after the animals had been exposed to the nanotubes. To the best of his group's knowledge, Castranova said that collagen formation will progress longer if test animals are allowed to live longer. "We were getting a fairly extensive pulmonary fibrosis, which was unique by the shape and the composition of that material," he said. "What was interesting is we got that without prolonged inflammation. With coal dust and silica you need prolonged inflammation to get fibrosis. These [carbon nanotube] materials are behaving somewhat differently." When asked what advice would he give industry about staying abreast of health research on nanomaterials, Castranova told conference delegates: "In the United States we have what's called a National Nanotechnology Initiative. NIOSH is part of that initiative, and what we've suggested is not only do you need to fund research and development of products but you need to fund research into potential toxicity so that these products can be used in an appropriate and responsible manner. "We think if we know enough we can protect the worker and the user. Right now we don't know enough."
	Copyright © 2006-2007 Sarah Belfield. All rights reserved.