Organ burden of inhaled nanoceria in a 2-year low-dose exposure study: dump or depot?

Abstract No detailed information on in vivo biokinetics of CeO2 nanoparticles (NPs) following chronic low-dose inhalation is available. The CeO2 burden for lung, lung-associated lymph nodes, and major non-pulmonary organs, blood, and feces, was determined in a chronic whole-body inhalation study in female Wistar rats undertaken according to OECD TG453 (6 h per day for 5 days per week for a 104 weeks with the following concentrations: 0, 0.1, 0.3, 1.0, and 3.0 mg/m3, animals were sacrificed after 3, 12, 24 months). Different spectroscopy methods (ICP-MS, ion-beam-microscopy) were used for the quantification of organ burden and for visualization of NP distribution patterns in tissues. After 24 months of exposure, the highest CeO2 lung burden (4.41 mg per lung) was associated with the highest aerosol concentration and was proportionally lower for the other groups in a dose-dependent manner. Imaging techniques confirmed the presence of CeO2 agglomerates of different size categories within lung tissue with a non-homogenous distribution. For the highest exposure group, after 24 months in total 1.2% of the dose retained in the lung was found in the organs and tissues analyzed in this study, excluding lymph nodes and skeleton. The CeO2 burden per tissue decreased from lungs > lymph nodes > hard bone > liver > bone marrow. For two dosage groups, the liver organ burden showed a low accumulation rate. Here, the liver can be regarded as depot, whereas kidneys, the skeleton, and bone marrow seem to be dumps due to steadily increasing NP burden over time.

[1]  Heinrich Ernst,et al.  Effects from a 90-day inhalation toxicity study with cerium oxide and barium sulfate nanoparticles in rats , 2017, Particle and Fibre Toxicology.

[2]  Christine Ruehl-Fehlert,et al.  Revised guides for organ sampling and trimming in rats and mice--Part 2. A joint publication of the RITA and NACAD groups. , 2004, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[3]  G. Travlos,et al.  Normal Structure, Function, and Histology of the Bone Marrow , 2006, Toxicologic pathology.

[4]  Christoph Fahrenson,et al.  Dosimetric Quantification of Coating-Related Uptake of Silver Nanoparticles. , 2017, Langmuir : the ACS journal of surfaces and colloids.

[5]  B. van Ravenzwaay,et al.  Time course of lung retention and toxicity of inhaled particles: short-term exposure to nano-Ceria , 2014, Archives of Toxicology.

[6]  Daniel Spemann,et al.  A quantitative study of the intracellular concentration of graphene/noble metal nanoparticle composites and their cytotoxicity. , 2014, Nanoscale.

[7]  Philip Demokritou,et al.  An in vivo and in vitro toxicological characterisation of realistic nanoscale CeO2 inhalation exposures , 2013, Nanotoxicology.

[8]  W. Koch,et al.  The Carcinogenic Effects of Carbon Black Particles and Tar–Pitch Condensation Aerosol after Inhalation Exposure of Rats , 1994 .

[9]  N. Konduru,et al.  Fate of Barium Sulfate Nanoparticles Deposited in the Lungs of Rats , 2019, Scientific Reports.

[10]  S. Aalapati,et al.  Toxicity and bio-accumulation of inhaled cerium oxide nanoparticles in CD1 mice , 2013, Nanotoxicology.

[11]  J L Mauderly,et al.  Comparative Pulmonary Toxicities and Carcinogenicities of Chronically Inhaled Diesel Exhaust and Carban Black in F344 Rats , 1995, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[12]  R. Henderson,et al.  Comparative Pulmonary Toxicities and Carcinogenicities of Chronically Inhaled Diesel Exhaust and Carbon Black in F344 Rats , 1995 .

[13]  J. Everitt,et al.  Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  F. E. Grubbs.  Sample Criteria for Testing Outlying Observations , 1950 .

[15]  H. Jungnickel,et al.  Simultaneous Quantification and Visualization of Titanium Dioxide Nanomaterial Uptake at the Single Cell Level in an In Vitro Model of the Human Small Intestine , 2019, Small Methods.

[16]  Philip Demokritou,et al.  Estimating the effective density of engineered nanomaterials for in vitro dosimetry , 2014, Nature Communications.

[17]  Wei Bai,et al.  Lung deposition and extrapulmonary translocation of nano-ceria after intratracheal instillation , 2010, Nanotechnology.

[18]  M. Wiemann,et al.  Application of short-term inhalation studies to assess the inhalation toxicity of nanomaterials , 2014, Particle and Fibre Toxicology.

[19]  P. Morrow,et al.  Dust overloading of the lungs: update and appraisal. , 1992, Toxicology and applied pharmacology.

[20]  Jordi Llop,et al.  Uptake, Biological Fate, and Toxicity of Metal Oxide Nanoparticles , 2014 .

[21]  J. Pauluhn.  Kinetic modeling of the retention and fate of inhaled cerium oxide nanoparticles in rats: The cumulative displacement volume of agglomerates determines the outcome , 2017, Regulatory toxicology and pharmacology : RTP.

[22]  P. Borm,et al.  Lung particle overload: old school –new insights? , 2015, Particle and Fibre Toxicology.

[23]  Wolfgang Koch,et al.  Chronic Inhalation Exposure of Wistar Rats and two Different Strains of Mice to Diesel Engine Exhaust, Carbon Black, and Titanium Dioxide , 1995 .

[24]  P. Morrow,et al.  Possible mechanisms to explain dust overloading of the lungs. , 1988, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[25]  J. A. Bond,et al.  Pulmonary toxicity of inhaled diesel exhaust and carbon black in chronically exposed rats. Part I: Neoplastic and nonneoplastic lung lesions. , 1994, Research report.

[26]  D. Spath.  Office of Environmental Health Hazard Assessment , 2000 .

[27]  K. Yavari,et al.  Production, quality control, and biodistribution studies of 141Ce-EDTMP as a potential bone pain palliation agent , 2018 .

[28]  G. Deves,et al.  Quantitative micro-analysis of metal ions in subcellular compartments of cultured dopaminergic cells by combination of three ion beam techniques , 2008, Analytical and bioanalytical chemistry.

[29]  K. Donaldson,et al.  Inhalation of poorly soluble particles. I. Differences in inflammatory response and clearance during exposure. , 2000, Inhalation toxicology.

[30]  Marike Kolossa-Gehring,et al.  The carcinogenic potential of nanomaterials, their release from products and options for regulating them. , 2011, International journal of hygiene and environmental health.

[31]  H. Jungnickel,et al.  Time-of-flight secondary ion mass spectrometry (ToF-SIMS)-based analysis and imaging of polyethylene microplastics formation during sea surf simulation. , 2016, The Science of the total environment.

[32]  Christine Ruehl-Fehlert,et al.  Revised guides for organ sampling and trimming in rats and mice--Part 3. A joint publication of the RITA and NACAD groups. , 2004, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[33]  Eileen Kuempel,et al.  An Approach to Risk Assessment for TiO2 , 2007, Inhalation toxicology.

[34]  Mark Bradley,et al.  Metal Oxide Nanoparticles Induce Unique Inflammatory Footprints in the Lung: Important Implications for Nanoparticle Testing , 2010, Environmental health perspectives.

[35]  Ralf J. M. Weber,et al.  Pulmonary toxicity of inhaled nano-sized cerium oxide aerosols in Sprague–Dawley rats , 2019, Nanotoxicology.

[36]  E. Grulke,et al.  Nanoceria biodistribution and retention in the rat after its intravenous administration are not greatly influenced by dosing schedule, dose, or particle shape , 2014 .

[37]  N. Konduru,et al.  Bioavailability, distribution and clearance of tracheally instilled, gavaged or injected cerium dioxide nanoparticles and ionic cerium , 2014 .

[38]  N. Konduru,et al.  Biokinetics and effects of barium sulfate nanoparticles , 2014, Particle and Fibre Toxicology.

[39]  B. van Ravenzwaay,et al.  Generation and Characterization of Test Atmospheres with Nanomaterials , 2007, Inhalation toxicology.

[40]  Flemming R Cassee,et al.  Comparative hazard identification of nano- and micro-sized cerium oxide particles based on 28-day inhalation studies in rats , 2014, Nanotoxicology.

[41]  Agnes G Oomen,et al.  Tissue distribution of inhaled micro- and nano-sized cerium oxide particles in rats: results from a 28-day exposure study. , 2012, Toxicological sciences : an official journal of the Society of Toxicology.

[42]  M. Wiemann,et al.  Detection of ZrO2 Nanoparticles in Lung Tissue Sections by Time-of-Flight Secondary Ion Mass Spectrometry and Ion Beam Microscopy , 2018, Nanomaterials.

[43]  S C Soderholm,et al.  Role of the alveolar macrophage in lung injury: studies with ultrafine particles. , 1992, Environmental health perspectives.

[44]  K. Yavari,et al.  Toxicity of nano and bulk forms of cerium oxide in different cell lines , 2018 .

[45]  K. P. Lee,et al.  Pulmonary response to impaired lung clearance in rats following excessive TiO2 dust deposition. , 1986, Environmental research.

[46]  Wendel Wohlleben,et al.  Nanospecific Guidance in REACH: A Comparative Physical-Chemical Characterization of 15 Materials with Methodical Correlations , 2013 .

[47]  Günter Oberdörster,et al.  TOXICOKINETICS AND EFFECTS OF FIBROUS AND NONFIBROUS PARTICLES , 2002, Inhalation toxicology.

[48]  I. Bechmann,et al.  The role of nerve inflammation and exogenous iron load in experimental peripheral diabetic neuropathy (PDN). , 2016, Metabolism: clinical and experimental.

[49]  M. Roller,et al.  Lung Tumor Risk Estimates from Rat Studies with Not Specifically Toxic Granular Dusts , 2006, Annals of the New York Academy of Sciences.

[50]  Thomas Nolte,et al.  Revised guides for organ sampling and trimming in rats and mice--part 1. , 2003, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[51]  Blanca Suarez-Merino,et al.  High throughput toxicity screening and intracellular detection of nanomaterials , 2016, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[52]  K. Ignatyev,et al.  Slow lung clearance and limited translocation of four sizes of inhaled iridium nanoparticles , 2017, Particle and Fibre Toxicology.

[53]  I. Govil.  Proton Induced X-ray Emission: A tool for non-destructive trace element analysis , 2001 .

[54]  J. Pauluhn.  Fate of inhaled Nano‐CeO2 revisited: Predicting the unpredictable , 2018, Regulatory toxicology and pharmacology : RTP.

[55]  R. T. Cullen, C. L. Tran, D. Buchanan, J. M. G. Da.  INHALATION OF POORLY SOLUBLE PARTICLES. I. DIFFERENCES IN INFLAMMATORY RESPONSE AND CLEARANCE DURING EXPOSURE , 2000 .

[56]  F. Cassee,et al.  The Yin: An adverse health perspective of nanoceria: uptake, distribution, accumulation, and mechanisms of its toxicity. , 2014, Environmental science. Nano.