Applied in conjunction with in vivo dosimetry models such as the Multipath Particle Deposition Model (MPPD), ISDD can be used as the initial step in translating cellular doses of nanoparticles between in vitro and in vivo systems (Teeguarden et al., 2014, below).
General Scheme for Translating Doses Across
in vitro and in vitro systems
This application area can grow as models of systemic particokinetics emerge.
In Vitro-In Vitro Dose Translation
Differences in media viscosity, temperature, and the height of media over cultured cells can influence cellular dose. Differences in media may also lead to differences in particle corona’s or particle agglomeration states between otherwise similar in vitro systems. Without some understanding of how significant these differences may be, differences in results across systems may be attributed to experimental variability rather than differences in dose.
Translating doses between in vitro systems is relatively straight forward when experimental measures of dose are not available for direct comparison. Particles should be characterized in the test media. The primary particle size, particle density, and agglomerate particle size should be measured. Ideally, the effective density of the agglomerates should also be measured (see Effective Density of Agglomerates tab). Media height and other parameters should also be acquired in both systems. Using these parameters as inputs, ISDD can be run and predicted doses can be compared and dose-response curves between systems be compared on the same units of dose.
In Vitro-In Vivo Dose Translation
Exposures, be they inhaled concentration (ppm), oral exposures (mass/kg), injected doses (mass/kg) or other route, cannot be compared directly to exposures in liquid systems (μg/ml). With advances computational nanomaterial dosimetry, namely ISDD, physiologically based pharmacokinetic (PBPK) models and inhalation particle dosimetry models such as MPPD, comparisons between in vitro and in vivo systems can be made with some confidence. These comparisons are best made using equivalent measures of dose and exposure between the systems, for example, the surface area of particles delivered to cells.
The framework and process for conducting dose translations across in vitro and in vivo systems is straight forward (see Figure), but can involve additional, non-trivial experimental work. An example of translation of doses between inhalation exposures in mice, in vitro cell culture studies, and human occupational studies was published by our group (Teeguarden et al., 2014, below). After calculating cellular doses for the in vitro systems (e.g. surface area per cell, or surface area of cells), doses are either measured directly, for example for systemic tissues like the liver, or calculated, for example for the inhalation route. The Multipath Particle Deposition Model, MPPD (ARA, Raleigh NC) is publically available computational dosimetry model for the human, monkey, rat and mouse respiratory tract. This model can be used, in conjunction with particle/aerosol characteristics, to calculate the delivered dose for particles in units of particle mass, number or surface area per lung surface area, and per macrophage. These metrics of exposure can then be compared directly to the same metric of exposure calculated for in vitro systems with ISDD, its equivalent, or measured directly.
Teeguarden, J.G., V.B. Mikheev, K.R. Minard, W.C. Forsythe, W. Wang, G. Sharma, N. Karin, S.C. Tilton, K.M. Waters, B. Asgharian, et al., Comparative iron oxide nanoparticle cellular dosimetry and response in mice by the inhalation and liquid cell culture exposure routes. Part Fibre Toxicol, 2014. 11(1): p. 46.