Journal of Occupational & Environmental Medicine:
Epidemiologic Research: Original Article
Feasibility of Biomarker Studies for Engineered Nanoparticles: What Can Be Learned From Air Pollution Research
Li, Ning PhD; Nel, Andre E. MD, PhD
From the Division of NanoMedicine, Department of Medicine (Dr Li, Dr Nel) and Center for Environmental Implications of Nanotechnology (Dr Nel), University of California Los Angeles, Los Angeles.
Address correspondence to: Ning Li, PhD, Division of NanoMedicine, Department of medicine, UCLA, 10833 Le Conte Ave, 52-175 CHS, Los Angeles, CA 90095; firstname.lastname@example.org.
Objective: Occupational exposure to engineered nanoparticles (NP) may pose health risks to the workers. This article is to discuss the feasibility of identifying biomarkers that are associated with NP exposure.
Methods: Scientific literature on the adverse health effects of ambient ultrafine particles (UFP) and NP was reviewed to discuss the feasibility of conducting biomarker studies to identify NP-induced early biological changes.
Results: Various approaches for biomarker studies have been identified, including potential injury pathways that need to be considered and the methodologies that may be used for such studies.
Conclusions: Although NP may have novel mechanisms of injury, much can be learned from our experience in studying UFP. Oxidative stress-related pathways can be an important consideration for identifying NP-associated biomarkers, and one of the most effective approaches for such studies may be proteome profiling.
Clinical Significance: Biomarker studies will provide valuable information to identify early biological events associated with the adverse health effects of engineered nanomaterials before the manifestation of clinical outcomes. This is particularly important for the health surveillance of workers who may be at higher risk due to their occupational settings.
The introduction of nanotechnology has brought great benefits to a wide span of areas in today's society and will continue to do so in the future, but it also brings many unknowns about its potential adverse health effects. The specific physicochemical characteristics of engineered nanoparticles (NP) may introduce health risks, which differ significantly from fine particles of the same chemical composition.1 Therefore, it is important to realize that certain groups of people, such as workers in nanotechnology-related fields, are at higher risk than the general population because of their close and constant contact with these materials and begin to take protective measures before an outbreak of serious clinical outcomes.
One of the strategies for preventing serious nanotoxicity from happening is to identify early biological events associated with exposure to harmful NP and then use that information for prevention. This can be achieved through biomarker studies in NP target organs/tissues or preferably in the biological fluid. While biomarker studies for NP toxicity are currently at their early stage, our experience in biomarker research for the incidental or ambient NP, aka, ultrafine particles (UFP), can be used to facilitate this process due to some similarities between UFP and certain NP. One of the injury mechanisms that are common to UFP and certain NP is the induction of oxidative stress and inflammatory responses by particles. In this communication, the feasibility of conducting NP-associated biomarker studies, based on what has been learned from air pollution research, will be discussed.
IMPORTANCE OF BIOMARKER STUDIES FOR NANOPARTICLE-RELATED OCCUPATIONAL SAFETY
Nanoparticles are less than 100 nm in size and are intentionally produced with specific characteristics required for their applications. Because of their unique size and physicochemical properties, such as surface area, shape, crystallinity, surface charge, reactive surface groups, dissolution rate, state of agglomeration, or dispersal, etc, NP are potentially more dangerous than larger particles of the same composition and may cause unanticipated adverse health effects to people who are exposed to these particles.1
Nanoparticle exposure can take place in almost all economic sectors, but occupational exposure in research laboratories and industries that manufacture, handle, use, and dispose these particles place the workers at potentially higher risk.2–4 Although there has been no report that link NP exposure to a definitive disease outcome, epidemiological studies have found hazardous respiratory effects through occupational exposure to carbon black and fumed silica.5–7 Another example of potential occupational hazard is the exposure to metal or metal oxide NP.8–10 Metal oxide NP are often used as industrial catalysts, and increased levels of these particles have been found in areas surrounding factories.8 There has been reported incidence of bronchitis, metal-fume fever, changes in lung function, and increased lung infection among welders.9,10 Metal-fume fever is a clinical syndrome that is presented as a flu-like illness characterized by self-limiting inflammation and oxidative stress response in the lung.11 It has been suggested that this condition is caused by the inhalation of highly concentrated metal oxide particles, particularly zinc oxide (ZnO).11–15 Given the growing use of NP and so many unknowns about their potential health effects, it is imperative to develop effective methods for assessing health risks associated with NP exposure. This is particularly important for the health surveillance and monitoring of workers who may be exposed to NP in the occupational setting.
Because of the short history of nanotechnology, currently, there is no published report that has established a definitive link between a disease outcome and exposure to a specific type of NP in humans. As it is almost certain that the growth of nanotechnology will outpace epidemiological studies, instead of waiting for these reports, an active approach would be to take precaution now so that the people at higher risk can be properly protected. One effective strategy to achieve this goal is to identify biomarkers associated with NP exposure. A “biomarker” is defined as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”16 Therefore, the role of biomarkers in assessing the health effects of NP is to link exposure to the disease outcomes by providing mechanistic indicators that are associated with early adverse effects of NP (Fig. 1). Although it is expected that it may take a long period of time to develop a panel of biomarkers that can be used as indicators of exposure-specific disease outcomes, identification of early biological responses related to injury pathways, based on our knowledge in air pollution research, would be a good starting point at this time.
OXIDATIVE STRESS-RELATED INFLAMMATION AS AN INJURY MECHANISM FOR THE TOXICITY OF ULTRAFINE PARTICLES AND CERTAIN NANOPARTICLES
In the last few years, in response to the rapid growth of nanotechnology, nanotoxicology has emerged as a unique field to study the toxicity of engineered nanomaterials (ENM), including NP, and to understand the injury mechanisms that are specifically related to the scale, dimension, and physicochemical characteristics of these materials.17,18 The concept of nanotoxicology is basically evolved from air pollution research, especially that on the incidental NP (ie, UFP). Although there are significant differences between UFP and NP in many aspects of their characteristics, there are certain similarities in the mechanisms of action and potential to produce adverse health effects between these two types of nanoscaled particles (Table 1).1,12,19
For example, two mechanisms that are common to UFP and several types of NP are the induction of oxidative stress and inflammatory response.1,12,19,20 That particle-induced oxidative stress is one of the major mechanisms for the adverse biological effects of UFP has been demonstrated in cellular, animal, and human studies.19,21–33 Inhaled UFP are capable of inducing oxidative stress in the lung as well as in systemic circulation. Particle-generated reactive oxygen species (ROS) and subsequent oxidative stress have been shown to be involved in many pathological conditions associated with respiratory and cardiovascular disease outcomes, including lung inflammation, asthma exacerbation, atherosclerosis, and thrombosis.19,30,32,34–38 Similarly, increasing evidence from cellular and animal studies has indicated that a number of NP also exert their proinflammatory and toxic effects through the same mechanisms.39–42
The prooxidative and proinflammatory properties have been observed in a number of metal oxide NP. Titanium dioxide (TiO2) NP, which have a number of industrial applications, are capable of generating ROS, inhibiting reduced glutathione (GSH), activating several Nrf2-mediated antioxidant enzymes (ie, heme oxygenase-1, thioredoxin reductase, GSH tranferase, and catalase), and upregulating inflammatory cytokine gene expression in human airway epithelial cells (BEAS-2B) and in rats.39,43–46 These prooxidative and proinflammatory effects of TiO2 are correlated to particle size, surface area, and composition.8,39,43,44,46–48 Copper oxide (CuO) NP that also have widespread applications have been shown to cause oxidative stress-mediated toxicity in a number of cultured cells.8,49–51 Exposure of airway epithelial cells to CuO NP induced a significant increase in 8-isoprostanes and the ratio of oxidized to total GSH in these cells, which was accompanied by decreased viability; this prooxidative effect of CuO NP could be effectively inhibited by coexposure to antioxidant resveratrol.8 Moreover, antioxidants, including N-acetyl cysteine (NAC) and catalase, could significantly attenuate the effect of CuO NP on the expression of plasminogen activator inhibitor-1, a protein involved in several cardiovascular diseases, in mouse pulmonary microvascular endothelial cells.52 The ROS generation by ZnO NP, the NP that are considered responsible for the metal-fume fever, in mouse macrophage and human bronchial epithelial cells could lead to oxidant injury, inflammatory response, and cell death.53 It has been suggested that the prooxidant activity of ZnO NP is the result of particle dissolution.54 Prevention of ZnO NP dissolution through Fe doping could effectively reduce the prooxidative and proinflammatory effects of these particles.54 In animal studies, long-term inhalation exposure to nickel hydroxide NP induced oxidative stress and inflammation in the lung and cardiovascular system in hyperlipidemic apoprotein E-deficient (ApoE−/−) mice.55 Intratracheal instillation of iron oxide NP in mice could lead to a significant decrease in GSH and an increase in proinflammatory cytokines in the bronchoalveolar lavage (BAL) fluid during acute response, while formation of microgranuloma, an indicator of chronic inflammation, was observed 28 days after exposure.56 In addition to metal or metal oxide NP, other NP such as silica, cationic polystyrene, and C60 fullerene have also been reported to exert prooxidative and proinflammatory in vitro and in vivo, including increased ROS production, induction of oxidative stress, activation of antioxidant and signaling pathways, and apoptosis.57–59
It is necessary to point out that not all NP cause inflammation via a mechanism involving oxidative stress.60,61 For example, it has been reported that while purified single-walled carbon nanotubes failed to generate ROS in cultured mouse macrophages, pharyngeal aspiration of these materials could induce progressive fibrosis and granuloma formation in mouse lung.60 Recently, Crouzier et al61 have demonstrated that intranasal instillation of purified double-walled carbon nanotubes elicited an inflammatory response in mice, which was accompanied by a decreased ROS production.61 Nonetheless, currently available evidence suggests that there are quite a few types of NP that exert their adverse health effects through similar mechanisms as UFP, including generation of oxidative stress and induction of inflammation. Thus, it is not impossible to initiate biomarker studies for these NP by focusing on these two well-defined injury pathways.
FEASIBILITY OF BIOMARKER STUDIES TO ASSESS NANOPARTICLE EXPOSURE-ASSOCIATED ADVERSE HEALTH EFFECTS
From the long history of air pollution research, various biomarkers linking air pollution exposure to its adverse effects in the respiratory and cardiovascular systems have been identified in human studies, and most of these biomarkers are associated with two major toxicological response pathways, oxidative stress and inflammation.62,63 For example, increased 8-isoprostane and melondialdehyde in exhaled breath condensate have been reported as biomarkers for local oxidative stress in the lung, whereas systemic oxidative stress markers include alteration in the levels of antioxidant enzymes and GSH in the blood.64–67 While increased levels of proinflammatory cytokines, cytokine receptors, and C-reactive protein have been considered the biomarkers associated with air pollution-induced systemic inflammation, platelet activation and increased expression of adhesion molecules have been identified as the biomarkers for the adverse cardiovascular effects of air pollution.62,64,65,68 For the NP that share similar injury mechanisms (ie, oxidative stress and inflammation) with UFP, it is theoretically feasible to conduct biomarker studies starting with similar approaches. For example, to assess the early events associated with exposure to these NP, the choice of potential biomarkers to be studied can include the changes that indicate local and systemic oxidative stress, systemic inflammation, and inflammatory response in NP target organs, such as those in respiratory, cardiovascular, and immune system.
Currently, there is no report of any definitive human disease that is caused by NP exposure. Therefore, it would not be practical and efficient to begin NP-associated biomarker identification in human studies. A more effective strategy would be using the step-wise approach to evolve NP-associated biomarker identification from cellular to animal and eventually to human studies, the same approach that has been used for studying air pollution-associated biomarkers. The advantage of cellular studies is that they will allow us to rapidly identify NP-induced early changes at biochemical and molecular levels, which may not be detected as disease endpoints in animal or in human studies, but may provide valuable information about the mechanistic basis for disease outcomes and help to guide further studies. In addition, cellular studies may also provide great potential for developing high throughput screening methods to accelerate biomarker studies. As the second step of studying NP exposure-related biomarkers, animal studies can further validate the findings from in vitro studies and have the advantage of being more physiologically relevant to disease outcomes in humans. Finally, biomarkers identified by cellular and animal studies will be validated in human studies, which have the ability to directly demonstrate the “real-life” disease endpoints and to guide the development of surveillance strategies for the workers who are potentially at higher risk of exposure to the adverse health effects of NP.
USE OF PROTEOMICS TO IDENTIFY BIOMARKERS ASSOCIATED WITH NANOPARTICLE EXPOSURE
While many biomarker studies are still carried out by using traditional biochemical and immunological assay methods, the technologies of mass spectrometry, high throughput screening, cell- and tissue-based DNA microarrays, and proteomics have provided great potential to accelerate this process. Among these new techniques, use of proteomics has been shown to be an effective approach for studying biomarkers induced by air pollutants, including ambient UFP.69–72 Proteomics uses high-throughput methodologies to study the complete profile of proteins in a given cell or tissue.73 Its ability to analyze global cellular response has made it possible to identify potential biomarkers that are associated with exposures to various environmental stimuli and stress.74 Thus, the discovery of new biomarkers by proteomics, combined with the traditional biological response endpoints, can become a powerful tool to assess the health effects and susceptibility factors related to environmental pollutants, including certain NP.73
Proteomics has been used as an analytical approach for identifying markers that are linked to exposures to environmental agents, as well as in disease conditions in both animals and humans, and proteome changes related to oxidative stress and inflammation have been identified under many of these conditions.71,75–78 Our own experience of using proteomics to study the biological effects of particulate air pollutants has allowed us to develop a oxidative stress response model that may explain the adverse health effects of particulate matter in the respiratory, cardiovascular, and immune system and to identify potential biomarkers associated with the adjuvant effect of UFP on allergic airway inflammation.71,77 Using this technology, we are able to study the biochemical and immunological changes associated with exposure to incidental NP (ie, diesel exhaust particles [DEP] and UFP), focusing on oxidative stress and inflammatory response. We have demonstrated that organic DEP extract is capable of inducing stratified oxidative stress responses in mouse macrophages and human bronchial epithelial cells that include the activation of antioxidant and detoxification defense systems, inflammation, and toxicity in cultured cells.71 This series of response is in parallel with a linear increase in newly expressed proteins measured by two-dimensional gel electrophoresis.71 By liquid chromatography-tandem mass spectrometry analysis, more than 30 proteins were identified as responsive to DEP-induced oxidative stress, suggesting that some of these proteins may serve as markers for exposure to prooxidative DEP chemicals.71,79 Other DEP-induced proteome changes include protein modification by nitrotyrosine, activation of the unfolding protein response, and increased expression of ATF4, an endoplasmic reticulum stress-associated transcription factor.69,71 In animal studies, we are able to identify oxidative stress-induced proteome changes in the BAL fluid and lung tissue in mouse asthma models.72,77 Our most recent study demonstrates that the expression of polymeric immunoglobulin receptor, complement C3, neutrophil gelatinase-associated lipocalin, chitinase 3-like protein 3 (Ym1), chitinase 3-like protein 4 (Ym2), and acidic mammalian chitinase (AMcase) in the lung is associated with the adjuvant effect of UFP on the primary immune response (allergic sensitization) and particulate oxidant potential.29,77 Increased Ym1 expression is also associated with the boosting effect of UFP on the secondary immune response in the “real-life” inhalation exposure study conducted near downtown Los Angeles.27 Moreover, our most recent study on NP has demonstrated oxidative stress-associated proteome changes in the BAL fluid from C57BL/6 mice that were exposed to ZnO NP via pharyngeal aspiration, suggesting that proteomics may also be used to identify biomarkers related to the exposure of certain NP (unpublished data). As it is evident that oxidative stress and inflammatory responses are also responsible for the toxicity of a number of NP, there is a great potential to use the technology of proteomics to identify the biomarkers associated with exposure to those NP that exert their adverse effects through these two injurious pathways.
In summary, the complicated physicochemical characteristics of ENM have brought an urgent need to study their potential adverse health effects, especially among workers who are exposed to these materials through daily work. While it will take a long period of time to link human disease outcomes to specific ENM exposures, we can take the advantage of our experience in air pollution research and available new technologies to study NP exposure-associated biological responses at biochemical, molecular, and cellular levels, a process known as biomarker studies. The ideal biomarkers for assessing environmental and occupational exposures should be able to provide strong mechanistic, molecular, or biochemical basis for the diseases, be exposure specific, reflect early adverse health effects, have clinical relevance, and easy to use. Although we are not able to identify the biomarkers that meet all these criteria at this time, it is feasible to study NP exposure-associated early biological events focusing on well-defined injury mechanisms such as oxidative stress and inflammation, which may be used as indicators of exposure to the hazardous NP.
This work is supported by NIH grants U19 AI-070453, U19ES019528, and RC2 ES-018766–01, EPA grant EPA-G2006-STAR-Q1, and Southern California Environmental Health Sciences Center Pilot Project grant H44764.
1. Nel A, Xia T, Madler L, Li N. Toxic potential of materials at the nanolevel. Science. 2006;311:622–627.
2. Schulte P, Geraci C, Zumwalde R, Hoover M, Kuempel E. Occupational risk management of engineered nanoparticles. J Occup Environ Hyg. 2008;5:239–249.
3. Schulte PA, Schubauer-Berigan MK, Mayweather C, Geraci CL, Zumwalde R, McKernan JL. Issues in the development of epidemiologic studies of workers exposed to engineered nanoparticles. J Occup Environ Med. 2009;51:323–335.
4. Schulte PA, Trout D, Zumwalde RD, et al. Options for occupational health surveillance of workers potentially exposed to engineered nanoparticles: state of the science. J Occup Environ Med. 2008;50:517–526.
5. Merget R, Bauer T, Kupper HU, et al. Health hazards due to the inhalation of amorphous silica. Arch Toxicol. 2002;75:625–634.
6. Buchte SF, Morfeld P, Wellmann J, Bolm-Audorff U, McCunney RJ, Piekarski C. Lung cancer mortality and carbon black exposure: a nested case-control study at a German carbon black production plant. J Occup Environ Med. 2006;48:1242–1252.
7. Wellmann J, Weiland SK, Neiteler G, Klein G, Straif K. Cancer mortality in German carbon black workers 1976–98. Occup Environ Med. 2006;63:513–521.
8. Fahmy B, Cormier SA. Copper oxide nanoparticles induce oxidative stress and cytotoxicity in airway epithelial cells. Toxicol In Vitro. 2009;23:1365–1371.
9. Antonini JM. Health effects of welding. Crit Rev Toxicol. 2003;33:61–103.
10. Antonini JM, Lewis AB, Roberts JR, Whaley DA. Pulmonary effects of welding fumes: review of worker and experimental animal studies. Am J Ind Med. 2003;43:350–360.
11. Luo JC, Hsu KH, Shen WS. Inflammatory responses and oxidative stress from metal fume exposure in automobile welders. J Occup Environ Med. 2009;51:95–103.
12. Xia T, Li N, Nel AE. Potential Health Impact of Nanoparticles. Annu Rev Public Health. 2009;30:137–150.
13. Antonini JM, Stone S, Roberts JR, et al. Effect of short-term stainless steel welding fume inhalation exposure on lung inflammation, injury, and defense responses in rats. Toxicol Appl Pharmacol. 2007;223:234–245.
14. Bydash J, Kasmani R, Naraharisetty K. Metal fume-induced diffuse alveolar damage. J Thorac Imaging. 2010;25:W27–W29.
15. Cooper RG. Zinc toxicology following particulate inhalation. Indian J Occup Environ Med. 2008;12:10–13.
16. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95.
17. Fischer HC, Chan WC. Nanotoxicity: the growing need for in vivo study. Curr Opin Biotechnol. 2007;18:565–571.
18. Donaldson K, Stone V, Tran CL, Kreyling W, Borm PJ. Nanotoxicology. Occup Environ Med. 2004;61:727–728.
19. Li N, Xia T, Nel AE. The role of oxidative stress in ambient particulate matter-induced lung diseases and its implications in the toxicity of engineered nanoparticles. Free Radic Biol Med. 2008;44:1689–1699.
20. Stone V, Johnston H, Clift MJ. Air pollution, ultrafine and nanoparticle toxicology: cellular and molecular interactions. IEEE Trans Nanobioscience. 2007;6:331–340.
21. Balakrishna S, Lomnicki S, McAvey KM, Cole RB, Dellinger B, Cormier SA. Environmentally persistent free radicals amplify ultrafine particle mediated cellular oxidative stress and cytotoxicity. Part Fibre Toxicol. 2009;6:11–24.
22. Li R, Ning Z, Majumdar R, et al. Ultrafine particles from diesel vehicle emissions at different driving cycles induce differential vascular pro-inflammatory responses: implication of chemical components and NF-kappa B signaling. Part Fibre Toxicol. 2010;7:6–17.
23. Araujo JA, Barajas B, Kleinman M, et al. Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress. Circ Res. 2008;102:589–596.
24. Li N, Sioutas C, Cho A, et al. Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage. Environ Health Perspect. 2003;111:455–460.
25. Mo Y, Wan R, Chien S, Tollerud DJ, Zhang Q. Activation of endothelial cells after exposure to ambient ultrafine particles: the role of NADPH oxidase. Toxicol Appl Pharmacol. 2009;236:183–193.
26. Weissenberg A, Sydlik U, Peuschel H, et al. Reactive oxygen species as mediators of membrane-dependent signaling induced by ultrafine particles. Free Radic Biol Med. 2010;49:597–605.
27. Li N, Harkema JR, Lewandowski RP, et al. Ambient ultrafine particles provide a strong adjuvant effect in the secondary immune response: implication for traffic-related asthma flares. Am J Physiol Lung Cell Mol Physiol. 2010;299:L374–L383.
28. Duvall RM, Norris GA, Dailey LA, et al. Source apportionment of particulate matter in the U.S. and associations with lung inflammatory markers. Inhal Toxicol. 2008;20:671–683.
29. Li N, Wang M, Bramble LA, et al. The adjuvant effect of ambient particulate matter is closely reflected by the particulate oxidant potential. Environ Health Perspect. 2009;117:1116–1123.
30. Oberdorster G. Pulmonary effects of inhaled ultrafine particles. Int Arch Occup Environ Health. 2001;74:1–8.
31. Peters A, Veronesi B, Calderon-Garciduenas L, et al. Translocation and potential neurological effects of fine and ultrafine particles a critical update. Part Fibre Toxicol. 2006;3:13–25.
32. Valavanidis A, Fiotakis K, Vlachogianni T. Airborne particulate matter and human health: toxicological assessment and importance of size and composition of particles for oxidative damage and carcinogenic mechanisms. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2008;26:339–362.
33. MacNee W, Donaldson K. How can ultrafine particles be responsible for increased mortality? Monaldi Arch Chest Dis. 2000;55:135–139.
34. Araujo JA, Nel AE. Particulate matter and atherosclerosis: role of particle size, composition and oxidative stress. Part Fibre Toxicol. 2009;6:24–42.
35. Delfino RJ, Sioutas C, Malik S. Potential role of ultrafine particles in associations between airborne particle mass and cardiovascular health. Environ Health Perspect. 2005;113:934–946.
36. Mills NL, Donaldson K, Hadoke PW, et al. Adverse cardiovascular effects of air pollution. Nat Clin Pract Cardiovasc Med. 2009;6:36–44.
37. Mills NL, Tornqvist H, Robinson SD, et al. Air pollution and atherothrombosis. Inhal Toxicol. 2007;19:81–89.
38. Scapellato ML, Lotti M. Short-term effects of particulate matter: an inflammatory mechanism? Crit Rev Toxicol. 2007;37:461–487.
39. Warheit DB, Webb TR, Reed KL, Frerichs S, Sayes CM. Pulmonary toxicity study in rats with three forms of ultrafine-TiO2 particles: differential responses related to surface properties. Toxicology. 2007;230:90–104.
40. Warheit DB, Reed KL, Sayes CM. A role for nanoparticle surface reactivity in facilitating pulmonary toxicity and development of a base set of hazard assays as a component of nanoparticle risk management. Inhal Toxicol. 2009;21:61–67.
41. Warheit DB, Sayes CM, Reed KL. Nanoscale and fine zinc oxide particles: can in vitro assays accurately forecast lung hazards following inhalation exposures? Environ Sci Technol. 2009;43:7939–7945.
42. Sayes CM, Reed KL, Warheit DB. Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles. Toxicol Sci. 2007;97:163–180.
43. Hussain S, Boland S, Baeza-Squiban A, et al. Oxidative stress and proinflammatory effects of carbon black and titanium dioxide nanoparticles: role of particle surface area and internalized amount. Toxicology. 2009;260:142–149.
44. Liang G, Pu Y, Yin L, et al. Influence of different sizes of titanium dioxide nanoparticles on hepatic and renal functions in rats with correlation to oxidative stress. J Toxicol Environ Health A. 2009;72:740–745.
45. Park EJ, Yi J, Chung KH, Ryu DY, Choi J, Park K. Oxidative stress and apoptosis induced by titanium dioxide nanoparticles in cultured BEAS-2B cells. Toxicol Lett. 2008;180:222–229.
46. Sayes CM, Wahi R, Kurian PA, et al. Correlating nanoscale titania structure with toxicity: a cytotoxicity and inflammatory response study with human dermal fibroblasts and human lung epithelial cells. Toxicol Sci. 2006;92:174–185.
47. Park EJ, Choi J, Park YK, Park K. Oxidative stress induced by cerium oxide nanoparticles in cultured BEAS-2B cells. Toxicology. 2008;245:90–100.
48. Madl AK, Pinkerton KE. Health effects of inhaled engineered and incidental nanoparticles. Crit Rev Toxicol. 2009;39:629–658.
49. Karlsson HL, Cronholm P, Gustafsson J, Moller L. Copper oxide nanoparticles are highly toxic: a comparison between metal oxide nanoparticles and carbon nanotubes. Chem Res Toxicol. 2008;21:1726–1732.
50. Karlsson HL, Gustafsson J, Cronholm P, Moller L. Size-dependent toxicity of metal oxide particles—a comparison between nano- and micrometer size. Toxicol Lett. 2009;188:112–118.
51. Ahamed M, Siddiqui MA, Akhtar MJ, Ahmad I, Pant AB, Alhadlaq HA. Genotoxic potential of copper oxide nanoparticles in human lung epithelial cells. Biochem Biophys Res Commun. 2010;396:578–583.
52. Yu M, Mo Y, Wan R, Chien S, Zhang X, Zhang Q. Regulation of plasminogen activator inhibitor-1 expression in endothelial cells with exposure to metal nanoparticles. Toxicol Lett. 2010;195:82–89.
53. Xia T, Kovochich M, Liong M, et al. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS Nano. 2008;2:2121–2134.
54. George S, Pokhrel S, Xia T, et al. Use of a rapid cytotoxicity screening approach to engineer a safer zinc oxide nanoparticle through iron doping. ACS Nano. 2010;4:15–29.
55. Kang GS, Gillespie PA, Gunnison A, Moreira AL, Tchou-Wong KM, Chen LC. A Long-term inhalation exposure to nickel nanoparticles exacerbated atherosclerosis in a susceptible mouse model. Environ Health Perspect. 2011;119:176–181.
56. Park EJ, Kim H, Kim Y, Yi J, Choi K, Park K. Inflammatory responses may be induced by a single intratracheal instillation of iron nanoparticles in mice. Toxicology. 2010;275:65–71.
57. Fujita K, Morimoto Y, Ogami A, et al. Gene expression profiles in rat lung after inhalation exposure to C60 fullerene particles. Toxicology. 2009;258:47–55.
58. Liu X, Sun J. Endothelial cells dysfunction induced by silica nanoparticles through oxidative stress via JNK/P53 and NF-kappaB pathways. Biomaterials. 2010;31:8198–8209.
59. Xia T, Kovochich M, Brant J, et al. Comparison of the abilities of ambient and manufactured nanoparticles to induce cellular toxicity according to an oxidative stress paradigm. Nano Lett. 2006;6:1794–1807.
60. Shvedova AA, Kisin ER, Mercer R, et al. Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice. Am J Physiol Lung Cell Mol Physiol. 2005;289:L698–L708.
61. Crouzier D, Follot S, Gentilhomme E, et al. Carbon nanotubes induce inflammation but decrease the production of reactive oxygen species in lung. Toxicology. 2010;272:39–45.
62. Delfino RJ, Staimer N, Tjoa T, et al. Associations of primary and secondary organic aerosols with airway and systemic inflammation in an elderly panel cohort. Epidemiology. 2010;21:892–902.
63. Grahame TJ, Schlesinger RB. Cardiovascular health and particulate vehicular emissions: a critical evaluation of the evidence. Air Qual Atmos Health. 2010;3:3–27.
64. Delfino RJ, Staimer N, Tjoa T, et al. Air pollution exposures and circulating biomarkers of effect in a susceptible population: clues to potential causal component mixtures and mechanisms. Environ Health Perspect. 2009;117:1232–1238.
65. Delfino RJ, Staimer N, Tjoa T, et al. Circulating biomarkers of inflammation, antioxidant activity, and platelet activation are associated with primary combustion aerosols in subjects with coronary artery disease. Environ Health Perspect. 2008;116:898–906.
66. Laumbach RJ, Kipen HM. Acute effects of motor vehicle traffic-related air pollution exposures on measures of oxidative stress in human airways. Ann N Y Acad Sci. 2010;1203:107–112.
67. Liu L, Poon R, Chen L, et al. Acute effects of air pollution on pulmonary function, airway inflammation, and oxidative stress in asthmatic children. Environ Health Perspect. 2009;117:668–674.
68. Duramad P, Tager IB, Holland NT. Cytokines and other immunological biomarkers in children's environmental health studies. Toxicol Lett. 2007;172:48–59.
69. Jung EJ, Avliyakulov NK, Boontheung P, Loo JA, Nel AE. Pro-oxidative DEP chemicals induce heat shock proteins and an unfolding protein response in a bronchial epithelial cell line as determined by DIGE analysis. Proteomics. 2007;7:3906–3918.
70. Kang X, Li N, Wang M, et al. Adjuvant effects of ambient particulate matter monitored by proteomics of bronchoalveolar lavage fluid. Proteomics;10:520–531.
71. Xiao GG, Wang M, Li N, Loo JA, Nel AE. Use of proteomics to demonstrate a hierarchical oxidative stress response to diesel exhaust particle chemicals in a macrophage cell line. J Biol Chem. 2003;278:50781–50790.
72. Zhang L, Wang M, Kang X, et al. Oxidative stress and asthma: proteome analysis of chitinase-like proteins and FIZZ1 in lung tissue and bronchoalveolar lavage fluid. J Proteome Res. 2009;8:1631–1638.
73. Sheehan D. The potential of proteomics for providing new insights into environmental impacts on human health. Rev Environ Health. 2007;22:175–194.
74. Lau AT, Chiu JF. Biomarkers of lung-related diseases: current knowledge by proteomic approaches. J Cell Physiol. 2009;221:535–543.
75. Xu NY, Zhang SP, Dong L, Nie JH, Tong J. Proteomic analysis of lung tissue of rats exposed to cigarette smoke and radon. J Toxicol Environ Health A. 2009;72:752–758.
76. Chang CC, Chen SH, Ho SH, Yang CY, Wang HD, Tsai ML. Proteomic analysis of proteins from bronchoalveolar lavage fluid reveals the action mechanism of ultrafine carbon black-induced lung injury in mice. Proteomics. 2007;7:4388–4397.
77. Kang X, Li N, Wang M, et al. Adjuvant effects of ambient particulate matter monitored by proteomics of bronchoalveolar lavage fluid. Proteomics. 2010;10:520–531.
78. de Torre C, Ying SX, Munson PJ, Meduri GU, Suffredini AF. Proteomic analysis of inflammatory biomarkers in bronchoalveolar lavage. Proteomics. 2006;6:3949–3957.
79. Wang M, Xiao GG, Li N, Xie Y, Loo JA, Nel AE. Use of a fluorescent phosphoprotein dye to characterize oxidative stress-induced signaling pathway components in macrophage and epithelial cultures exposed to diesel exhaust particle chemicals. Electrophoresis. 2005;26:2092–2108.
This article has been cited 4 time(s).
Inhalation ToxicologyToxicological effects of PM0.25-2.0 particles collected from a photocopy center in three human cell linesInhalation Toxicology
Nanosafe 2012: International Conferences on Safe Production and Use of NanomaterialsOverview of Risk Management for Engineered NanomaterialsNanosafe 2012: International Conferences on Safe Production and Use of Nanomaterials
NanotoxicologyNanoparticles from photocopiers induce oxidative stress and upper respiratory tract inflammation in healthy volunteersNanotoxicology
Journal of Occupational and Environmental MedicineEngineered Nanomaterials: Learning from the Past, Planning for the FutureJournal of Occupational and Environmental Medicine
©2011The American College of Occupational and Environmental Medicine