ISDD: A computational model of particle sedimentation, diffusion and target cell dosimetry for in vitro toxicity studies
Open Access
- 30 November 2010
- journal article
- Published by Springer Science and Business Media LLC in Particle and Fibre Toxicology
- Vol. 7 (1), 36
- https://doi.org/10.1186/1743-8977-7-36
Abstract
The difficulty of directly measuring cellular dose is a significant obstacle to application of target tissue dosimetry for nanoparticle and microparticle toxicity assessment, particularly for in vitro systems. As a consequence, the target tissue paradigm for dosimetry and hazard assessment of nanoparticles has largely been ignored in favor of using metrics of exposure (e.g. μg particle/mL culture medium, particle surface area/mL, particle number/mL). We have developed a computational model of solution particokinetics (sedimentation, diffusion) and dosimetry for non-interacting spherical particles and their agglomerates in monolayer cell culture systems. Particle transport to cells is calculated by simultaneous solution of Stokes Law (sedimentation) and the Stokes-Einstein equation (diffusion). The In vitro Sedimentation, Diffusion and Dosimetry model (ISDD) was tested against measured transport rates or cellular doses for multiple sizes of polystyrene spheres (20-1100 nm), 35 nm amorphous silica, and large agglomerates of 30 nm iron oxide particles. Overall, without adjusting any parameters, model predicted cellular doses were in close agreement with the experimental data, differing from as little as 5% to as much as three-fold, but in most cases approximately two-fold, within the limits of the accuracy of the measurement systems. Applying the model, we generalize the effects of particle size, particle density, agglomeration state and agglomerate characteristics on target cell dosimetry in vitro. Our results confirm our hypothesis that for liquid-based in vitro systems, the dose-rates and target cell doses for all particles are not equal; they can vary significantly, in direct contrast to the assumption of dose-equivalency implicit in the use of mass-based media concentrations as metrics of exposure for dose-response assessment. The difference between equivalent nominal media concentration exposures on a μg/mL basis and target cell doses on a particle surface area or number basis can be as high as three to six orders of magnitude. As a consequence, in vitro hazard assessments utilizing mass-based exposure metrics have inherently high errors where particle number or surface areas target cells doses are believed to drive response. The gold standard for particle dosimetry for in vitro nanotoxicology studies should be direct experimental measurement of the cellular content of the studied particle. However, where such measurements are impractical, unfeasible, and before such measurements become common, particle dosimetry models such as ISDD provide a valuable, immediately useful alternative, and eventually, an adjunct to such measurements.Keywords
This publication has 47 references indexed in Scilit:
- A 21st Century Paradigm for Evaluating the Health Hazards of Nanoscale Materials?Toxicological Sciences, 2009
- Three-dimensional real-timein vivomagnetic particle imagingPhysics in Medicine & Biology, 2009
- Macrophage Responses to Silica Nanoparticles are Highly Conserved Across Particle SizesToxicological Sciences, 2008
- Perchlorate and Radioiodide Kinetics Across Life Stages in the Human: Using PBPK Models to Predict Dosimetry and Thyroid Inhibition and Sensitive Subpopulations Based on Developmental StageJournal of Toxicology and Environmental Health, Part A, 2007
- An Approach to Risk Assessment for TiO2Inhalation Toxicology, 2007
- Forum Series: Research Strategies for Safety Evaluation of NanomaterialsToxicological Sciences, 2005
- Tomographic imaging using the nonlinear response of magnetic particlesNature, 2005
- PBPK Model for Radioactive Iodide and Perchlorate Kinetics and Perchlorate-Induced Inhibition of Iodide Uptake in HumansToxicological Sciences, 2004
- A Multiple-Path Model of Fiber Deposition in the Rat LungToxicological Sciences, 1998
- Pacemaker cell types in the rabbit sinus node: A correlative ultrastructural and electrophysiological studyJournal of Molecular and Cellular Cardiology, 1984