Nanotoxicology Not Expected to Occur When Proteins Bind to Large Particles

EDITORIAL 727 Occup Environ Med: first published as 10.1136/oem.2004.013243 on 18 August 2004. Downloaded from

Toxicology and sustained release of drugs.12 ...... Furthermore, because of their size and large surface area, NP binding to protein may result in a series of consequences Nanotoxicology not expected to occur when proteins bind to large particles. These could K Donaldson, V Stone, C L Tran, W Kreyling, P J A Borm include: ...... N NP-protein complexes may be more mobile and, via protein metabolism, A new frontier in particle toxicology relevant to both the NPs may gain access to sites which workplace and general environment and to consumer safety large particles would not reach. N Enhanced protein degradation at the he revolution in nanotechnology is groups as well as the German parlia- large surface area of NPs may lead to set to bring advantages in areas of ment.2 Both European Union and functional changes of those proteins Tour lives as diverse as engineering, European Science Foundation have also which would not occur at the rela- information technology, and diagnos- initiated activities to map the risks and tively small surface area of large 67 tics. Part of this will necessitate large opportunities from nanotechnology.3 So particles. scale production of nanoparticles with far these studies illustrate the enormous new formulations and surface properties opportunities of nanotechnology to give to meet novel demands. Our current impetus to progress in both life sciences DO NANOPARTICLES REPRESENT knowledge of the toxicology of nano- and information technology. However, A TOXICOLOGICAL HAZARD? particles and nanotubes is poor but there have already been a number of Adverse effects of NP are likely to occur suggests that nanoparticles may be able papers highlighting the potential envir- in very different scenarios. For NP made to have adverse effects at their portal of onmental hazards arising from nano- and handled in bulk there is potential entry, for example, the lungs, but that technology.4–7 While some of the for lung exposure. We are already some nanoparticles may also escape the products that will contain nanoparticles exposed to large numbers of ambient normal defences and translocate from are likely to have them fundamentally NP in environmental air pollution13 their portal of entry to have diverse bound up in the structure, there is the where the NP component has been the effects in other target organs. We potential for exposure to NP and nano- focus of much research as one of the suggest that a discipline of nanotoxicol- materials throughout the product chain likely drivers of adverse health effects.14 ogy be built up to address the new during manufacture, application, and For some NP, such as those in sunblock potential threats that widespread use of waste management; subsequently there cream, dermal exposure is already new nanoparticles could bring in sup- is a need for a toxicology that can assess occurring and the range of different port of the growth of a safe and the likely harm they may cause. NP in creams is likely to increase.15 16 sustainable nanotechnology industry. Nanoparticles in food are reported to WHAT IS A NANOPARTICLE? cross into the gut lymphatics and redis- 8 tribute to other organs more readily THE NANOTECHNOLOGY Particle toxicology is a mature science than larger particles.17 18 A huge class REVOLUTION which has addressed the mechanisms of lung injury caused by nanoparticles, and of NP are designed to be introduced There has been a great deal of interest http://oem.bmj.com/ directly into the body for diagnostic and in the scientific and general community the term ultrafine particles has been in therapeutic reasons,19 and for these in ‘‘the nanotechnology revolution’’. use for some time to denote nanoparti- 9 there needs to be toxicology on the Nanotechnology can be defined as: cles. There is no size cut-off below which particles suddenly become harm- particles as well as for the drugs that ful, in the lungs at least. This is because they contain. Carbon nanotubes are ‘‘… the manipulation, precision harmful particles have their effects as a long thin structures which can have placement, measurement, model- consequence of two factors that act diameters of a few nanometres, while ling, or manufacture of sub-100 the length can be up to many thousands

together to determine their potential to on September 30, 2021 by guest. Protected copyright. 1 nanometer scale matter …’’ cause harm: their large surface area, and of nanometres.20 These could have very the reactivity or intrinsic toxicity of the unusual toxicological properties, in that This manipulation of matter at the surface.10 11 It is self evident that the they share shape characteristics of both nanoscale will have diverse effects in smaller particles are, the more surface fibres and NPs; such limited toxicology manufacture, engineering, especially area they have per unit mass; therefore as presently exists supports the conten- energy engineering, environmental any intrinsic toxicity of the particle tion that these may be harmful to the technology, information technology, surface will be emphasised. As particles lungs.21 health and pharmaceuticals, etc. become generally smaller their likeli- There is a considerable existing data- Currently there is production of a wide hood of causing harm to the lung base in the lung particle toxicology range of nanoparticles (NP) of different increases. NP are currently available in literature that shows NP of various sorts types and different properties which will a variety of compositions that range to have extra toxicity,22 by which we be tested for their utility in various from very simple—almost pure carbon mean that the same material in the form applications. It is envisaged that those or TiO2—to very complex structures, of NP is more toxic than in the form of found useful will be further developed where surface modifications are applied. larger, still respirable, particles. Of spe- into large scale manufacture. Any tech- Some of the most complex NP are likely cial concern is the apparent ability of NP nology before introducing it to the to be produced for therapeutic purposes, to redistribute from their site of deposi- marketplace and into the product chain with characteristics that are designed to tion. Thus following inhalation expo- needs careful evaluation with regard to give them properties of prolonging cir- sure, NP have been reported to travel via its sustainability and risk perception. A culation in the blood, homing to specific the nasal nerves to the brain,23 24 as has number of studies have been conducted organs or tissues, escape from phagocy- been described for polio virus,25 and to by US and EU nanotechnology expert tosis, blood-brain barrier translocation, gain access to the blood and other

www.occenvmed.com 728 EDITORIAL Occup Environ Med: first published as 10.1136/oem.2004.013243 on 18 August 2004. Downloaded from organs as reviewed by Kreyling and co- toxicity of nanoparticles, with special 4 Colvin VL. The potential environmental impact of 6 engineered nanomaterials. Nat Biotechnol workers. reference to extra-pulmonary transport 2003;21:1166–70. Very small particles and structures and burden of particles at sites distant 5 Brumfiel G. Nanotechnology: a little knowledge. could have a range of effects that are not to the portal of entry. Additionally, there Nature 2003;424:246–8. seen with conventional particles For is a strong need for a focused research 6 Kreyling W, Semmler M, Moller W. Dosimetry and toxicology of ultrafine particles. J Aerosol instance they may not be detected by programme directed towards fully Med, In press.. the normal phagocytic defences, allow- understanding the relation of size and 7 Borm PJA, Kreyling W. Toxicological hazards of ing them to gain access to the blood or surface area on the deposition, translo- nanoparticles for drug delivery. Journal of Nanoscience and Nanotechnology, In press. the nervous system. Very small particles cation, and toxicity of small particles. In 8 Donaldson K, Borm PJA. Particle paradigms. are smaller than some molecules and order to facilitate development of exper- Inhal Toxicol 2000;12(suppl 3):1–6. could act like haptens to modify protein tise in this multidisciplinary area, we 9 Donaldson K, Stone V, Clouter A, et al. Ultrafine particles. Occup Environ Med structures, either altering their function recommend that test results should be 2001;58:211–16. or rendering them antigenic, raising the exchanged via virtual networks that 10 Tran CL, Buchanan D, Cullen RT, et al. Inhalation potential for autoimmune effects. integrate toxicologists, material scien- of poorly soluble particles. II. Influence of particle surface area on inflammation and clearance. The same size of particle may be very tists, chemists, physicists, and medical Inhal Toxicol 2000;12:1113–26. different in its ability to translocate or doctors. 11 Donaldson K, Tran CL. Inflammation caused have any of the effects mentioned above We believe that efforts to untangle by particles and fibres. Inhal Toxicol 2002;14:5–27. if its surface is altered chemically for science and science fiction regarding the 12 Oberdorster G, Utell MJ. Ultrafine particles in the special industrial or therapeutic applica- risks from nanotechnology are needed urban air: to the respiratory tract—and beyond? tion. A hallmark example in particle and that a focus on the potential Environ Health Perspect 2002;110:A440–1. toxicology is quartz, which has been 13 Maynard RL, Howard B, eds. Particulate matter: harmful effects of NP is both timely properties and effects upon health. Oxford: Bios 26 shown to have a variable hazard, and necessary. The importance of nano- Scientific Publishers, 1999. mediated by a very small level (,0.1%) technology to the economy and to our 14 Donaldson K, MacNee W. Potential mechanisms of surface impurity.27 28 Considering that future wellbeing is beyond debate, but of adverse pulmonary and cardiovascular effects of particulate air pollution (PM10). Int J Hyg surface modification is the fastest grow- its potential adverse impacts need to be Environ Health 2001;203:411–15. ing market for bulk NP application, the studied along the same lines. A disci- 15 Tan MH, Commens CA, Burnett L, et al. A pilot various effects of these treatments on pline of nanotoxicology would make an study on the percutaneous absorption of microfine titanium dioxide from sunscreens. the toxicology of NPs should be inves- important contribution to the develop- Australas J Dermatol 1996;37:185–7. tigated. ment of a sustainable and safe nano- 16 Pinnell SR, Fairhurst D, Gillies R, et al. Microfine technology. zinc oxide is a superior sunscreen ingredient to microfine titanium dioxide. Dermatol Surg NANOTOXICOLOGY Occup Environ Med 2004;61:727–728. 2000;26:309–14. NP have greater potential to travel doi: 10.1136/oem.2004.013243 17 Jani P, Halbert GW, Langridge J, et al. through the organism than other mate- Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation and particle size rials or larger particles. The various ...... dependency. J Pharm Pharmacol interactions of NP with fluids, cells, Authors’ affiliations 1990;42:821–6. and tissues need to be considered, K Donaldson, ELEGI Colt Laboratory, Wilkie 18 Hillery AM, Jani PU, Florence AT. Comparative, Building, University of Edinburgh, Medical quantitative study of lymphoid and non-lymphoid starting at the portal of entry and then uptake of 60 nm polystyrene particles. J Drug via a range of possible pathways School, Teviot Place, Edinburgh EH9 8AG, UK Target 1994;2:151–6. towards target organs. The potential V Stone, School of Life Sciences, Napier 19 Duncan R. The dawning era of polymer for significant biological response at University, 10 Colinton Rd, Edinburgh therapeutics. Nat Rev Drug Discov EH10 5DT, UK 2003;2:347–60. each of these sites requires investiga- http://oem.bmj.com/ C L Tran, Institute of Occupational Medicine, 20 Sun YP, Fu K, Lin Y, et al. Functionalized carbon nanotubes: properties and applications. Acc tion. In addition, at the site of final Research Park North, Edinburgh EH14 4AP, retention in the target organ(s), NP may Chem Res 2002;35:1096–104. UK 21 Warheit DB, Laurence BR, Reed KL, et al. trigger mediators which then may acti- W Kreyling, GSF National Research Center Comparative pulmonary toxicity assessment of vate inflammatory or immunological for Environment & Health, Institute for single-wall carbon nanotubes in rats. Toxicol Sci responses. Importantly NP may also Inhalation Biology, Focus Network: Aerosols 2004;77:117–25. 22 Donaldson K, Tran CL, MacNee W. Deposition enter the blood or the central nervous and Health, PO Box 1129, D-85758 and effects of fine and ultrafine particles in the system, where they have the potential to Neuherberg/Munich, Germany respiratory tract. The European Respiratory directly affect cardiac and cerebral func- P J A Borm, Centre of Expertise in Life Monograph 2002;7:77–92. on September 30, 2021 by guest. Protected copyright. 23 Kreuter J, Shamenkov D, Petrov V, et al. tions. Sciences (CEL), Hogeschool Zuyd, PO Box 2606, 6401 DC Heerlen, Netherlands Apolipoprotein-mediated transport of We therefore propose that a new nanoparticle-bound drugs across the blood-brain subcategory of toxicology—namely barrier. J Drug Target 2002;10:317–25. Correspondence to: Professor K Donaldson, 24 Oberdorster G, Sharp Z, Elder AP, et al. nanotoxicology—be defined to address ELEGI Colt Laboratory, Wilkie Building, Translocation of inhaled ultrafine particles to the gaps in knowledge and to specifically University of Edinburgh, Medical School, Teviot brain. Inhal Toxicol 2004;16:437–45. address the special problems likely to be Place, Edinburgh EH9 8AG, UK; 25 Bodian D, Howe HA. Experimental studies on [email protected] intraneural spread of poliomyelitis virus. Bulletin caused by nanoparticles. Under the of the Johns Hopkins Hospital heading of nanotoxicology we consider 1941;LXVIII:248–67. that protocols should be developed for REFERENCES 26 Donaldson K, Borm PJ. The quartz hazard: a testing of all materials in the nanoscale, variable entity. Ann Occup Hyg 1 Meyer M, Persson O, Power Y, and the 1998;42:287–94. where there is the potential for sub- nanotechnology expert group. Mapping 27 Schins RP, Duffin R, Hohr D, et al. 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