An Approach to Tentative Reference Levels Setting for Nanoparticles in the Workroom Air Based on Comparing Their Toxicity with That of Their Micrometric Counterparts: A Case Study of Iron Oxide Fe3O4
We overview the state of the art in the field of safe exposure levels setting for nanomaterials together with the previously published results of our experimental investigations characterizing comparative toxicity of the iron oxide F e 3 O 4 (magnetite) in the form of microparticles and nanoparticles of different size and comparative activity of the defensive alveolar phagocytosis response to their pulmonary deposition. An approach to the substantiation of acceptable workplace exposure limits of metallic nanoparticles is discussed and, specifically, the tentative reference level for magnetite nanoparticles is recommended. 1. Introduction The development of nanotechnologies has led to the emergence of a lot of materials containing nanoscale particles. By convention, a particle is defined as being in the nano-scale range if it has at least one linear dimension not exceeding 100？nm. Nanoparticles (NPs) of various materials find wide application in different industries, in medicine, and in science. In particular, magnetite (Fe3O4) NPs are increasingly often used in medicine and biology as selective carriers of drugs to organs, as markers controlled by an external magnetic field, as cancer cell killers (thanks to local hyperthermia caused by the heating of these NPs in a external variable magnetic field), as a contrast material in magnetic resonance tomography, and so forth. Looking for advance in general nanotoxicology, uncoated engineered NPs of any iron oxide present an interesting research object because such research brings us nearer to the answer of the important question of whether or not a material which is extremely low toxic both in bulk and in the micrometer particle size range may become so toxic in the nanostate, that it may present a serious hazard to human health in the course of its production and use. A good evidence of the rather low toxicity of usual (not nano-scale) iron oxides is that they are allowed by the Joint Expert Committee on Food Additives (JECFA) for use as colouring agents due to their being practically innocuous at a systematic daily intake of up to 0.5？mg/kg. Theoretical grounds for expecting a sharp increase in the toxicity of a substance in the form of NPs have been highlighted by many authors (e.g., [1–4]), and it is not among the objectives of this paper to discuss these grounds. It should be noted, however, that analysis of a great number of published data obtained in actual research supports the statement that “this common perception of greater nanoparticle toxicity is based on a limited number of studies” [5].
References
[1]
K. Donaldson, V. Stone, C. L. Tran, W. Kreyling, and P. J. A. Borm, “Nanotoxicology,” Occupational and Environmental Medicine, vol. 61, no. 9, pp. 727–728, 2004.
[2]
G. Oberd？rster, E. Oberd？rster, and J. Oberd？rster, “Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles,” Environmental Health Perspectives, vol. 113, no. 7, pp. 823–839, 2005.
[3]
N. G. Bastús, E. Casals, S. Vázquez-Campos, and V. Puntes, “Reactivity of engineered inorganic nanoparticles and carbon nanostructures in biological media,” Nanotoxicology, vol. 2, no. 3, pp. 99–112, 2008.
[4]
N. Li, T. Xia, and A. E. Nel, “The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticles,” Free Radical Biology and Medicine, vol. 44, no. 9, pp. 1689–1699, 2008.
[5]
D. B. Warheit, K. L. Reed, and C. M. Sayes, “A role for surface reactivity in TiO2 and quartz-related nanoparticle pulmonary toxicity,” Nanotoxicology, vol. 3, no. 3, pp. 181–187, 2009.
[6]
D. B. Warheit, T. R. Webb, V. L. Colvin, K. L. Reed, and C. M. Sayes, “Pulmonary bioassay studies with nanoscale and fine-quartz particles in rats: toxicity is not dependent upon particle size but on surface characteristics,” Toxicological Sciences, vol. 95, no. 1, pp. 270–280, 2007.
[7]
H. L. Karlsson, J. Gustafsson, P. Cronholm, and L. M？ller, “Size-dependent toxicity of metal oxide particles-A comparison between nano- and micrometer size,” Toxicology Letters, vol. 188, no. 2, pp. 112–118, 2009.
[8]
R. A. Yokel and R. C. MacPhail, “Engineered nanomaterials: exposures, hazards, and risk prevention,” Journal of Occupational Medicine and Toxicology, vol. 6, no. 1, article 7, 2011.
[9]
V. Murashov, P. Schulte, C. Geraci, and J. Howard, “Regulatory approaches to worker protection in nanotechnology industry in the USA and European union,” Industrial Health, vol. 49, no. 3, pp. 280–296, 2011.
[10]
A. Groso, A. Petri-Fink, A. Magrez, M. Riediker, and T. Meyer, “Management of nanomaterials safety in research environment,” Particle and Fibre Toxicology, vol. 7, Article ID 40, 2010.
[11]
P. van Broekhuizen, “Dealing with uncertainties in the nanotech workplace practice: making the precautionary approach operational,” Journal of Biomedical Nanotechnology, vol. 7, no. 1, pp. 15–17, 2011.
[12]
B. A. Katsnelson and L. I. Privalova, “Recruitment of phagocytizing cells into the respiratory tract as a response to the cytotoxic action of deposited particles,” Environmental Health Perspectives, vol. 55, pp. 313–325, 1984.
[13]
L. I. Privalova, B. A. Katsnelson, and A. B. Osipenko, “Response of a phagocyte cell system to products of macrophage breakdown as a probable mechanism of alveolar phagocytosis adaptation to deposition of particles of different cytotoxicity,” Environmental Health Perspectives, vol. 35, pp. 205–218, 1980.
[14]
L. I. Privalova, B. A. Katsnelson, and L. N. Yelnichnykh, “Some peculiarities of the pulmonary phagocytotic response: dust retention kinetics and silicosis development during long term exposure of rats to high quartz dust levels,” British Journal of Industrial Medicine, vol. 44, no. 4, pp. 228–235, 1987.
[15]
L. I. Privalova, B. A. Katsnelson, N. Y. Sharapova, and N. S. Kislitsina, “On the relationship between activation and breakdown of macrophages in the pathogenesis of silicosis (An overview),” Medicina del Lavoro, vol. 86, no. 6, pp. 511–521, 1995.
[16]
B. A. Katsnelson, L. K. Konyscheva, N. Y. Sharapova, and L. I. Privalova, “Prediction of the comparative intensity of pneumoconiotic changes caused by chronic inhalation exposure to dusts of different cytotoxicity by means of a mathematical model,” Occupational and Environmental Medicine, vol. 51, no. 3, pp. 173–180, 1994.
[17]
B. A. Katsnelson, O. G. Alekseyeva, L. I. Privalova, and E. V. Polzik, Pneumoconioses: The Pathogenesis and Biological Prophylaxis, The Urals Division of the RAS, Ekaterinburg, Russia, 1995.
[18]
B. A. Katsnelson, L. K. Konysheva, L. I. Privalova, and N. Y. Sharapova, “Quartz dust retention in rat lungs under chronic exposure simulated by a multicompartmental model: further evidence of the key role of the cytotoxicity of quartz particles,” Inhalation Toxicology, vol. 9, no. 8, pp. 703–715, 1997.
[19]
B. Katsnelson, L. I. Privalova, S. V. Kuzmin et al., “Some peculiarities of pulmonary clearance mechanisms in rats after intratracheal instillation of magnetite ( ) suspensions with different particle sizes in the nanometer and micrometer ranges: are we defenseless against nanoparticles?” International Journal of Occupational and Environmental Health, vol. 16, no. 4, pp. 508–524, 2010.
[20]
K. H. Kilburn, “Alveolar clearance of particles. A bullfrog lung model,” Archives of Environmental Health, vol. 18, no. 4, pp. 556–563, 1969.
[21]
B. A. Katsnelson, T. D. Degtyareva, I. I. Minigalieva et al., “Subchronic systemic toxicity and bioaccumulation of nano- and microparticles following repeated intraperitoneal administration to rats,” International Journal of Toxicology, vol. 30, no. 1, pp. 59–68, 2011.
[22]
B. A. Katsnelson, L. I. Privalova, M. P. Sutunkova et al., “The “in vivo” interaction between iron oxide nanoparticles and alveolar macrophages,” Bulletin of Experimental Biology and Medicine, vol. 152, no. 5, pp. 627–631, 2012.
[23]
B. A. Katsnelson, L. I. Privalova, and M. P. Sutunkova, “Uptake of some metallic nanoparticles by, and their impact on pulmonary macrophages in vivo as viewed by optical, atomic force, and transmission electron microscopy,” Journal of Nanomedicine & Nanotechnology, vol. 3, no. 1, pp. 1–8, 2012.
[24]
L. M. Petin, “Establishment of the maximum permissible concentrations of silica-containing condensation aerosols,” Meditsina Truda I Promyshlennaya Ekologiya, no. 6, pp. 28–33, 1978.
[25]
E. Ying and H. M. Hwang, “In vitro evaluation of the cytotoxicity of iron oxide nanoparticles with different coatings and different sizes in A3 human T lymphocytes,” Science of the Total Environment, vol. 408, no. 20, pp. 4475–4481, 2010.
[26]
A. C. Allison, “Lysosomes and the toxicity of particulate pollutants,” Archives of Internal Medicine, vol. 128, no. 1, pp. 131–139, 1971.
[27]
K. Tsuchiya, N. Nitta, A. Sonoda et al., “Histological study of the biodynamics of iron oxide nanoparticles with different diameters,” International Journal of Nanomedicine, vol. 6, pp. 1587–1594, 2011.
[28]
CDC and NIOSH, Current Intelligence Bulletin 63: Occupational Exposure to Titanium Dioxide, US Department of Health and Human Services, NIOSH, 2011.
[29]
Safe Work Australia, Engineered Nanomaterials: Feasibility of establishing exposure standards and using control banding in Australia, 2010.
