thesis
Old materials, new challenges? Fumed silica has been used as an anti-caking agent in foods for several decades. Does new research suggest that the use of this engineered nanomaterial needs to be re-examined, asks Andrew D. Maynard. The term ‘engineered nanomaterial’ often conjures up images of esoteric substances that are the product of recent advances in atomic-scale material design. Yet there are many rather more mundane engineered nanomaterials that have been around for decades, and tend not to catch the limelight. That is, until someone has the audacity to question their safety. I was reminded of this recently at a meeting on bio–nano interactions, hosted by the Royal Society in the UK1. In among the typical conversations that occur at such events, the discussion touched on the safety of food-grade synthetic amorphous silica (SAS). This caused me to pause and think. I’ve often used SAS as an example of a safe nanomaterial, and here was evidence that cast doubt on what I thought I knew to be true. I found myself, I must confess, facing a conundrum. SAS is an engineered nanomaterial that has been in commerce for over half a century. In 1942, Harry Kloepfer — a chemist at Degussa AG (now Evonik) —
invented a process for generating fumed silica2. This led to the launch of Aerosil® SAS in 1943 — an amorphous fumed silica powder with primary particle diameters between 4 and 20 nm. SAS materials, such as Aerosil® SAS and Cab-O-Sil®, are used in a multitude of applications ranging from functional fillers in polymers to strengthening additives in car tyres3. They are also used as additives in powdered food products that aid flowability and reduce caking. In the United States, for example, the Food and Drug Administration allows up to 2% by weight of silica to be added to food products as an anti-caking agent 4 — purchase a jar of chilli powder and the chances are it will contain a small amount of SAS. SAS comes with a provenance of safety testing and safe use. In 2006, a review of SAS toxicity from the European Center for Ecotoxicology and Toxicology of Chemicals summarized what was then the state of understanding on SAS safety 5. According to the review, in acute ingestion studies using
100 nm
Transmission electron micrograph of a representative Aerosil® 200 primary particle aggregate. Image courtesy of Darren Dunphy and Jeff Brinker, the University of New Mexico and UCLA Center for Environmental Implications of Nanotechnology. 658
rats, no signs of toxicity were observed at doses of up to 5,000 mg SiO2 kg−1 body weight (equivalent to a 70 kg adult eating 350 g of SAS). In 90-day studies, no adverse effects were seen in rats with diets containing over 1,000 mg amorphous SiO2 kg−1 day−1 (equivalent to a 70 kg adult eating 70 g of SAS per day for 90 days). In 2008, this review was cited extensively in a longer submission to the US Environmental Protection Agency Nanoscale Material Stewardship Program by the Synthetic Amorphous Silica and Silicate Industry Association6. The submission concluded that, “Overall, SAS is a substance that does not pose any unique toxicity due to is nanostructure or other physical– chemical properties. Over 60 years of manufacture and use of SAS has shown that SAS presents little (if any) health risks when handled properly.” Both the report of the European Center for Ecotoxicology and Toxicology of Chemicals and the report of the Synthetic Amorphous Silica and Silicate Industry Association were prepared by industry. The reports used studies from industry, as well as peer-reviewed academic research. So they may be viewed as presenting an overly optimistic perspective on SAS safety. However, the data, methodologies and analysis are sound, and are borne out by both the regulatory status of SAS in the United States, and the lack of evidence of adverse effects among people exposed to the substance. In contrast, a 2012 paper by Haiyuan Zhang and colleagues published in the Journal of the American Chemistry Society suggested that fumed silica may be more toxic than previously assumed7. Zhang and co-workers subjected fumed and colloidal forms of SAS to a battery of characterization and in vitro toxicity studies. In one set of experiments, they used a sample of Aerosil® (the fumed silica), and in a parallel set, they used amorphous silica particles formed in-house through condensation of silanol groups in aqueous solution (the colloidal silica). Both materials had a primary particle diameter of around 16 nm, although the Aerosil® particles were sintered into fractal-like
NATURE NANOTECHNOLOGY | VOL 9 | SEPTEMBER 2014 | www.nature.com/naturenanotechnology
© 2014 Macmillan Publishers Limited. All rights reserved
thesis structures with effective diameters up to several hundred nanometres. Despite the physical and chemical similarities, the fumed silica was shown to be biologically more active than its colloidal counterpart. Whereas data for colloidal silica indicated that the material was not toxic at the concentrations used, fumed silica was shown to lead to the production of hydroxyl radicals and reactive oxygen species, and to show dose-dependent red blood cell haemolysis.
Purchase a jar of chilli powder and the chances are it will contain a small amount of synthetic amorphous silica. Physicochemical characterization of the two material types identified a relatively high concentration of strained siloxane rings on the surface of fumed silica particles, but not on the colloidal particles. These were most likely associated with the highly energetic production process used to form the fumed silica. Zhang and colleagues hypothesized that the presence of these strained rings was associated with the observed toxicity in the fumed silica particles. It was the Zhang et al. data that initially caused me to pause and think at the Royal Society meeting. Their study found unexpected indicators of toxicity that were plausibly associated with new insights into a structural component of fumed silica. And these data highlight plausible mechanisms of action that could lead to harm. Could these data indicate an as-yet unrecognized toxicity associated with fumed silica in food products? It’s possible. Yet caution is needed in overinterpreting the data. The gastrointestinal tract is a harsh and complex environment, and jumping to conclusions from in vitro studies would be at best naive. Addressing this gap between in vitro behaviour and impact in a living organism, Meike van der Zande and colleagues recently published the findings of a study specifically focused on the toxicity of ingested SAS8. Rats were fed foodgrade SAS, and a reference SAS material selected by the Organization for Economic Cooperation and Development, for up to 84 days. The upper doses were high at 2,500 mg kg−1 day−1 (equivalent to a 70 kg person eating 175 g in their diet every day, for nearly three months; to put this into context, a typical serving of breakfast cereal is 30 g). Although very few adverse indicators of health impact were observed, possible accumulation was seen in the
spleen at the highest concentrations of food-grade SAS. With the Organization for Economic Cooperation and Developmentselected SAS, fibrosis was observed in the animals’ livers. Although the data from van der Zande et al. and Zhang et al. suggest further research is warranted on ingested fumed silica, the research does not, on its own, provide actionable insights into the likelihood of harm — especially given significant differences in physiology and substance uptake from the gastrointestinal tract in humans and rats. This gets to the heart of the conundrum I faced at the Royal Society meeting: when surprising new insights emerge on possible material health risks, where does the responsibility lie for ensuring that new research is conducted on material safety, without this research influencing consumers and regulators before there is plausible justification for action? Or to put it more succinctly, how can we encourage exploratory risk research without it prematurely impacting consumer and regulatory decisions? It could be argued of course that decisions should be made based on early indicators of harm, and that precaution is necessary in cases like this. This is a powerful argument given a long history of potentially avoidable health and environmental impacts from commercial products. Yet when actions can potentially have far-reaching consequences on lives and livelihoods — as tighter regulation of fumed silica in food products inevitably would — how are appropriate trigger points for action defined? I would argue that the balance of evidence on ingested fumed silica isn’t even close to a trigger point as yet, and that premature action could cause a lot more harm than good. Yet, from a research perspective, there is every justification to explore further the possibility of fumed silica causing harm if used inappropriately. Unfortunately, as the debate over the safety of engineered nanomaterials becomes an increasingly public one, the distinction between exploratory research and actionable data all too easily becomes muddled. As a result, it is not uncommon for early-stage research into potential hazards to translate into vocal calls for regulatory action. This muddling is only exacerbated when the debate is framed in terms of novel behaviour and unknown risks9. Within this shifting dynamic of public discourse around emergent risks, responsibility for clarifying the distinction between discovery and action must fall in part on the scientific community. With
NATURE NANOTECHNOLOGY | VOL 9 | SEPTEMBER 2014 | www.nature.com/naturenanotechnology
© 2014 Macmillan Publishers Limited. All rights reserved
increasing pressure to demonstrate the relevance of research, it’s all too easy to extrapolate from interesting findings to implied calls for action. Yet what is academically fascinating can quickly translate into unwarranted doubt and concern among constituencies, and from there to poorly conceived decisions. Rather, the privilege of scientific insight should come with the responsibility to use this insight with care and consideration.
How can we encourage exploratory risk research without it prematurely impacting consumer and regulatory decisions? Based on the available evidence, fumed silica in food is acceptably safe. It may be that future research leads to a re-evaluation of its safe use. But it would at this point be irresponsible to question its use on the grounds of a cell-based study that did not address behaviour in the gastrointestinal tract, and because the material falls under the umbrella of ‘engineered nanomaterials’. It would be equally irresponsible to curb research on the potential hazards and risks of fumed silica under the assumption that there is nothing else to discover about how it behaves in the body. And it would most definitely be irresponsible for researchers not to support consumers, policymakers, the media and others in understanding the distinction between exploratory research and that aimed at informing decisions. ❐ Andrew D. Maynard is at the Risk Science Center, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, Michigan 48109, USA. e-mail: [email protected] References
1. https://royalsociety.org/events/2014/04/bio-nano 2. http://history.evonik.com/sites/geschichte/en/inventions/aerosil/ pages/default.aspx 3. European Commission Joint Research Centre Synthetic Amorphous Silicon Dioxide (NM-200, NM-201, NM-202, NM-203, NM-204): Characterisation and Physico-Chemical Properties. JRC Scientific and Policy Reports, JRC 83506 (Publications Office of the European Union, 2013). 4. Code of Federal Regulations Title 21, Vol. 3, 21CFR172.480 (US FDA, 2013); www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfCFR/CFRSearch.cfm?fr=172.480 5. European Center for Ecotoxicology and Toxicology of Chemicals Synthetic Amorphous Silica (CAS No. 7631-86-9), JACC No. 51 (ECETOC, 2006); available at http://go.nature.com/2BmLc1 6. Synthetic Amorphous Silica and Silicates Industry Association Nanoscale Materials Stewardship Program (NMSP) Voluntary Submittal Package for Synthetic Amorphous Silica CAS No. 7631-86-9 (SASSI, 2008); www.epa.gov/oppt/nano/sassia.pdf 7. Zhang, H. Y. et al. J. Am. Chem. Soc. 134, 15790–15804 (2012). 8. van der Zande, M. et al. Part. Fibre Toxicol. 11, 8 (2014). 9. Maynard, A. Nature Nanotech. 9, 409–410 (2014).
659
Old materials, new challenges? Fumed silica has been used as an anti-caking agent in foods for several decades. Does new research suggest that the use of this engineered nanomaterial needs to be re-examined, asks Andrew D. Maynard. The term ‘engineered nanomaterial’ often conjures up images of esoteric substances that are the product of recent advances in atomic-scale material design. Yet there are many rather more mundane engineered nanomaterials that have been around for decades, and tend not to catch the limelight. That is, until someone has the audacity to question their safety. I was reminded of this recently at a meeting on bio–nano interactions, hosted by the Royal Society in the UK1. In among the typical conversations that occur at such events, the discussion touched on the safety of food-grade synthetic amorphous silica (SAS). This caused me to pause and think. I’ve often used SAS as an example of a safe nanomaterial, and here was evidence that cast doubt on what I thought I knew to be true. I found myself, I must confess, facing a conundrum. SAS is an engineered nanomaterial that has been in commerce for over half a century. In 1942, Harry Kloepfer — a chemist at Degussa AG (now Evonik) —
invented a process for generating fumed silica2. This led to the launch of Aerosil® SAS in 1943 — an amorphous fumed silica powder with primary particle diameters between 4 and 20 nm. SAS materials, such as Aerosil® SAS and Cab-O-Sil®, are used in a multitude of applications ranging from functional fillers in polymers to strengthening additives in car tyres3. They are also used as additives in powdered food products that aid flowability and reduce caking. In the United States, for example, the Food and Drug Administration allows up to 2% by weight of silica to be added to food products as an anti-caking agent 4 — purchase a jar of chilli powder and the chances are it will contain a small amount of SAS. SAS comes with a provenance of safety testing and safe use. In 2006, a review of SAS toxicity from the European Center for Ecotoxicology and Toxicology of Chemicals summarized what was then the state of understanding on SAS safety 5. According to the review, in acute ingestion studies using
100 nm
Transmission electron micrograph of a representative Aerosil® 200 primary particle aggregate. Image courtesy of Darren Dunphy and Jeff Brinker, the University of New Mexico and UCLA Center for Environmental Implications of Nanotechnology. 658
rats, no signs of toxicity were observed at doses of up to 5,000 mg SiO2 kg−1 body weight (equivalent to a 70 kg adult eating 350 g of SAS). In 90-day studies, no adverse effects were seen in rats with diets containing over 1,000 mg amorphous SiO2 kg−1 day−1 (equivalent to a 70 kg adult eating 70 g of SAS per day for 90 days). In 2008, this review was cited extensively in a longer submission to the US Environmental Protection Agency Nanoscale Material Stewardship Program by the Synthetic Amorphous Silica and Silicate Industry Association6. The submission concluded that, “Overall, SAS is a substance that does not pose any unique toxicity due to is nanostructure or other physical– chemical properties. Over 60 years of manufacture and use of SAS has shown that SAS presents little (if any) health risks when handled properly.” Both the report of the European Center for Ecotoxicology and Toxicology of Chemicals and the report of the Synthetic Amorphous Silica and Silicate Industry Association were prepared by industry. The reports used studies from industry, as well as peer-reviewed academic research. So they may be viewed as presenting an overly optimistic perspective on SAS safety. However, the data, methodologies and analysis are sound, and are borne out by both the regulatory status of SAS in the United States, and the lack of evidence of adverse effects among people exposed to the substance. In contrast, a 2012 paper by Haiyuan Zhang and colleagues published in the Journal of the American Chemistry Society suggested that fumed silica may be more toxic than previously assumed7. Zhang and co-workers subjected fumed and colloidal forms of SAS to a battery of characterization and in vitro toxicity studies. In one set of experiments, they used a sample of Aerosil® (the fumed silica), and in a parallel set, they used amorphous silica particles formed in-house through condensation of silanol groups in aqueous solution (the colloidal silica). Both materials had a primary particle diameter of around 16 nm, although the Aerosil® particles were sintered into fractal-like
NATURE NANOTECHNOLOGY | VOL 9 | SEPTEMBER 2014 | www.nature.com/naturenanotechnology
© 2014 Macmillan Publishers Limited. All rights reserved
thesis structures with effective diameters up to several hundred nanometres. Despite the physical and chemical similarities, the fumed silica was shown to be biologically more active than its colloidal counterpart. Whereas data for colloidal silica indicated that the material was not toxic at the concentrations used, fumed silica was shown to lead to the production of hydroxyl radicals and reactive oxygen species, and to show dose-dependent red blood cell haemolysis.
Purchase a jar of chilli powder and the chances are it will contain a small amount of synthetic amorphous silica. Physicochemical characterization of the two material types identified a relatively high concentration of strained siloxane rings on the surface of fumed silica particles, but not on the colloidal particles. These were most likely associated with the highly energetic production process used to form the fumed silica. Zhang and colleagues hypothesized that the presence of these strained rings was associated with the observed toxicity in the fumed silica particles. It was the Zhang et al. data that initially caused me to pause and think at the Royal Society meeting. Their study found unexpected indicators of toxicity that were plausibly associated with new insights into a structural component of fumed silica. And these data highlight plausible mechanisms of action that could lead to harm. Could these data indicate an as-yet unrecognized toxicity associated with fumed silica in food products? It’s possible. Yet caution is needed in overinterpreting the data. The gastrointestinal tract is a harsh and complex environment, and jumping to conclusions from in vitro studies would be at best naive. Addressing this gap between in vitro behaviour and impact in a living organism, Meike van der Zande and colleagues recently published the findings of a study specifically focused on the toxicity of ingested SAS8. Rats were fed foodgrade SAS, and a reference SAS material selected by the Organization for Economic Cooperation and Development, for up to 84 days. The upper doses were high at 2,500 mg kg−1 day−1 (equivalent to a 70 kg person eating 175 g in their diet every day, for nearly three months; to put this into context, a typical serving of breakfast cereal is 30 g). Although very few adverse indicators of health impact were observed, possible accumulation was seen in the
spleen at the highest concentrations of food-grade SAS. With the Organization for Economic Cooperation and Developmentselected SAS, fibrosis was observed in the animals’ livers. Although the data from van der Zande et al. and Zhang et al. suggest further research is warranted on ingested fumed silica, the research does not, on its own, provide actionable insights into the likelihood of harm — especially given significant differences in physiology and substance uptake from the gastrointestinal tract in humans and rats. This gets to the heart of the conundrum I faced at the Royal Society meeting: when surprising new insights emerge on possible material health risks, where does the responsibility lie for ensuring that new research is conducted on material safety, without this research influencing consumers and regulators before there is plausible justification for action? Or to put it more succinctly, how can we encourage exploratory risk research without it prematurely impacting consumer and regulatory decisions? It could be argued of course that decisions should be made based on early indicators of harm, and that precaution is necessary in cases like this. This is a powerful argument given a long history of potentially avoidable health and environmental impacts from commercial products. Yet when actions can potentially have far-reaching consequences on lives and livelihoods — as tighter regulation of fumed silica in food products inevitably would — how are appropriate trigger points for action defined? I would argue that the balance of evidence on ingested fumed silica isn’t even close to a trigger point as yet, and that premature action could cause a lot more harm than good. Yet, from a research perspective, there is every justification to explore further the possibility of fumed silica causing harm if used inappropriately. Unfortunately, as the debate over the safety of engineered nanomaterials becomes an increasingly public one, the distinction between exploratory research and actionable data all too easily becomes muddled. As a result, it is not uncommon for early-stage research into potential hazards to translate into vocal calls for regulatory action. This muddling is only exacerbated when the debate is framed in terms of novel behaviour and unknown risks9. Within this shifting dynamic of public discourse around emergent risks, responsibility for clarifying the distinction between discovery and action must fall in part on the scientific community. With
NATURE NANOTECHNOLOGY | VOL 9 | SEPTEMBER 2014 | www.nature.com/naturenanotechnology
© 2014 Macmillan Publishers Limited. All rights reserved
increasing pressure to demonstrate the relevance of research, it’s all too easy to extrapolate from interesting findings to implied calls for action. Yet what is academically fascinating can quickly translate into unwarranted doubt and concern among constituencies, and from there to poorly conceived decisions. Rather, the privilege of scientific insight should come with the responsibility to use this insight with care and consideration.
How can we encourage exploratory risk research without it prematurely impacting consumer and regulatory decisions? Based on the available evidence, fumed silica in food is acceptably safe. It may be that future research leads to a re-evaluation of its safe use. But it would at this point be irresponsible to question its use on the grounds of a cell-based study that did not address behaviour in the gastrointestinal tract, and because the material falls under the umbrella of ‘engineered nanomaterials’. It would be equally irresponsible to curb research on the potential hazards and risks of fumed silica under the assumption that there is nothing else to discover about how it behaves in the body. And it would most definitely be irresponsible for researchers not to support consumers, policymakers, the media and others in understanding the distinction between exploratory research and that aimed at informing decisions. ❐ Andrew D. Maynard is at the Risk Science Center, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, Michigan 48109, USA. e-mail: [email protected] References
1. https://royalsociety.org/events/2014/04/bio-nano 2. http://history.evonik.com/sites/geschichte/en/inventions/aerosil/ pages/default.aspx 3. European Commission Joint Research Centre Synthetic Amorphous Silicon Dioxide (NM-200, NM-201, NM-202, NM-203, NM-204): Characterisation and Physico-Chemical Properties. JRC Scientific and Policy Reports, JRC 83506 (Publications Office of the European Union, 2013). 4. Code of Federal Regulations Title 21, Vol. 3, 21CFR172.480 (US FDA, 2013); www.accessdata.fda.gov/scripts/cdrh/cfdocs/ cfCFR/CFRSearch.cfm?fr=172.480 5. European Center for Ecotoxicology and Toxicology of Chemicals Synthetic Amorphous Silica (CAS No. 7631-86-9), JACC No. 51 (ECETOC, 2006); available at http://go.nature.com/2BmLc1 6. Synthetic Amorphous Silica and Silicates Industry Association Nanoscale Materials Stewardship Program (NMSP) Voluntary Submittal Package for Synthetic Amorphous Silica CAS No. 7631-86-9 (SASSI, 2008); www.epa.gov/oppt/nano/sassia.pdf 7. Zhang, H. Y. et al. J. Am. Chem. Soc. 134, 15790–15804 (2012). 8. van der Zande, M. et al. Part. Fibre Toxicol. 11, 8 (2014). 9. Maynard, A. Nature Nanotech. 9, 409–410 (2014).
659
