Nanoparticle toxicokinetics in the nose : an assessment of risk

In recent years there has been a dramatic increase in the number of nanomaterials being developed, thus increasing the need for hazard assessment methods beyond the capacity of toxicological screening methods using animals. Current in vitro assays have a number of shortcomings, which were addressed...

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Main Author: Kumar, Abhinav
Published: King's College London (University of London) 2013
Subjects:
611
Online Access:http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.628305
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spelling ndltd-bl.uk-oai-ethos.bl.uk-6283052016-06-21T03:29:44ZNanoparticle toxicokinetics in the nose : an assessment of riskKumar, Abhinav2013In recent years there has been a dramatic increase in the number of nanomaterials being developed, thus increasing the need for hazard assessment methods beyond the capacity of toxicological screening methods using animals. Current in vitro assays have a number of shortcomings, which were addressed in this thesis. These include: (i) high dependence on immortalized cell lines, (ii) inaccurate dosimetry descriptors, (iii) poor robustness of assay systems, and (iv) hyperoxic culture conditions. A method for harvesting viable human nasal epithelial cells using a washout technique was developed to provide squamous epithelial cells for use in culture assays. However, poor proliferation of these cells in vitro limited their use in toxicological assays. A particokinetic model was developed to relate the ’delivered dose’, i.e. the number of nanoparticles reaching immortalized airway cell layers by gravitational force and diffusional mechanisms, to toxicological endpoints measured in vitro. This model was applied to a panel of rigorously characterized nanoparticles (CuO, TiC>2, polystyrene and in-house manufactured lipid nanocapsules) and the results provided compelling evidence that the delivered dose is a more appropriate dose descriptor for cell-based toxicity assays than the widely used nominal dose, as it reflects the number of particles (or their equivalent surface area) available to interact with the cell layer over a given exposure time. The results were confirmed in two airway epithelial cell lines RPMI 2650 and A549 after 6 and 24 h using two standard toxicological end-points. However, when cells were cultured in normoxic (for the respiratory tract) oxygen concentration, 13%, as opposed to the standard culture conditions of 21% they were found to be more responsive to nanoparticle exposure in terms of both production of reactive oxygen species and reduced cell viability. This suggests that standard incubation conditions of 21% oxygen provide a baseline of oxidative stress within a cell culture system that induces adaptive mechanisms and reduces their sensitivity to materials that exert adverse effects through oxidative stress.611King's College London (University of London)http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.628305https://kclpure.kcl.ac.uk/portal/en/theses/nanoparticle-toxicokinetics-in-the-nose(8f4cfda8-c5fa-48b1-9def-d59a6821b354).htmlElectronic Thesis or Dissertation
collection NDLTD
sources NDLTD
topic 611
spellingShingle 611
Kumar, Abhinav
Nanoparticle toxicokinetics in the nose : an assessment of risk
description In recent years there has been a dramatic increase in the number of nanomaterials being developed, thus increasing the need for hazard assessment methods beyond the capacity of toxicological screening methods using animals. Current in vitro assays have a number of shortcomings, which were addressed in this thesis. These include: (i) high dependence on immortalized cell lines, (ii) inaccurate dosimetry descriptors, (iii) poor robustness of assay systems, and (iv) hyperoxic culture conditions. A method for harvesting viable human nasal epithelial cells using a washout technique was developed to provide squamous epithelial cells for use in culture assays. However, poor proliferation of these cells in vitro limited their use in toxicological assays. A particokinetic model was developed to relate the ’delivered dose’, i.e. the number of nanoparticles reaching immortalized airway cell layers by gravitational force and diffusional mechanisms, to toxicological endpoints measured in vitro. This model was applied to a panel of rigorously characterized nanoparticles (CuO, TiC>2, polystyrene and in-house manufactured lipid nanocapsules) and the results provided compelling evidence that the delivered dose is a more appropriate dose descriptor for cell-based toxicity assays than the widely used nominal dose, as it reflects the number of particles (or their equivalent surface area) available to interact with the cell layer over a given exposure time. The results were confirmed in two airway epithelial cell lines RPMI 2650 and A549 after 6 and 24 h using two standard toxicological end-points. However, when cells were cultured in normoxic (for the respiratory tract) oxygen concentration, 13%, as opposed to the standard culture conditions of 21% they were found to be more responsive to nanoparticle exposure in terms of both production of reactive oxygen species and reduced cell viability. This suggests that standard incubation conditions of 21% oxygen provide a baseline of oxidative stress within a cell culture system that induces adaptive mechanisms and reduces their sensitivity to materials that exert adverse effects through oxidative stress.
author Kumar, Abhinav
author_facet Kumar, Abhinav
author_sort Kumar, Abhinav
title Nanoparticle toxicokinetics in the nose : an assessment of risk
title_short Nanoparticle toxicokinetics in the nose : an assessment of risk
title_full Nanoparticle toxicokinetics in the nose : an assessment of risk
title_fullStr Nanoparticle toxicokinetics in the nose : an assessment of risk
title_full_unstemmed Nanoparticle toxicokinetics in the nose : an assessment of risk
title_sort nanoparticle toxicokinetics in the nose : an assessment of risk
publisher King's College London (University of London)
publishDate 2013
url http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.628305
work_keys_str_mv AT kumarabhinav nanoparticletoxicokineticsinthenoseanassessmentofrisk
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