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Concordance between in vitro and in vivo dosimetry in the proinflammatory effects of low-toxicity, low-solubility particles: the key role of the proximal alveolar region.

Authors
Donaldson-K; Borm-PJ; Oberdorster-G; Pinkerton-KE; Stone-V; Tran-CL
Source
Inhal Toxicol 2008 Jan; 20(1):53-62
NIOSHTIC No.
20033231
Abstract
We previously demonstrated the importance of the surface area burden as the key dose metric in the elicitation of inflammation in rat lungs by low-solubility, low-toxicity particles (LSLTP). We have now explored the dosimetry of LSLTP in vitro using epithelial cell interleukin (IL)-8 gene expression as a surrogate for potential of particles to cause inflammation. The proximal alveolar region (PAR) of the lung has been identified as a key site for the retention of respirable particles, as it receives high deposition but has slow clearance compared to the larger airways. For these reasons, a few days after exposure to particles the residual dose is concentrated in the PAR region. Re-expressing our rat lung data as particle surface area burden per unit of PAR surface area we obtained a threshold value for onset of inflammation of 1 cm(2)/cm(2). We carried out dose responses in vitro for onset of IL-8 gene expression with the same particles as we had used in vivo. When we expressed the in vitro dose as surface area dose per unit A549cell culture surface area, we obtained a threshold of 1 cm(2)/cm(2). This concordance between proinflammatory effects in vivo (PMN in BAL) and in vitro (epithelial IL-8 gene expression) confirms and supports the utility of the particle surface area metric and the importance of the PAR. These studies also open the way for future in vitro approaches to studying proinflammatory effects of a range of toxic particles based on sound dosimetry that complements animal use in particle toxicology.
Keywords
Epidemiology; Respiration; Risk-analysis; Risk-factors; Laboratory-animals; Cell-biology; Cell-differentiation; Cell-function; Cell-metabolism; Cellular-function; Cellular-reactions; Genes; Genetic-factors; Genotoxic-effects; Lung-cells; Lung-disorders; Lung-function; Lung-irritants; Particle-aerodynamics; Particulate-dust; Particulates; Toxicopathology
Contact
K. Donaldson, MRC/University of Edinburgh Centre for Inflammation Research, ELEGI Colt Laboratory, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK
CODEN
INHTE5
Publication Date
20080101
Document Type
Journal Article
Email Address
ken.donaldson@ed.ac.uk
Funding Type
Agriculture; Cooperative Agreement
Fiscal Year
2008
NTIS Accession No.
NTIS Price
Identifying No.
Cooperative-Agreement-Number-U50-OH-007550
Issue of Publication
1
ISSN
0895-8378
Source Name
Inhalation Toxicology
State
CA
Performing Organization
University of California - Davis
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