Comparative iron oxide nanoparticle cellular dosimetry and response in mice by the inhalation and liquid cell culture exposure routes

Abstract

BackgroundToxicity testing the rapidly growing number of nanomaterials requires large scale use of in vitro systems under the presumption that these systems are sufficiently predictive or descriptive of responses in in vivo systems for effective use in hazard ranking. We hypothesized that improved relationships between in vitro and in vivo models of experimental toxicology for nanomaterials would result from placing response data in vitro and in vivo on the same dose scale, the amount of material associated with cells.MethodsBalb/c mice were exposed nose-only to an aerosol (68.6 nm CMD, 19.9 mg/m3, 4 hours) generated from of 12.8 nm superparamagnetic iron oxide particles (SPIO). Target cell doses were calculated, histological evaluations conducted, and biomarkers of response were identified by global transcriptomics. Representative murine epithelial and macrophage cell types were exposed in vitro to the same material in liquid suspension for four hours and levels of nanoparticle regulated cytokine transcripts identified in vivo were quantified as a function of measured nanoparticle cellular dose.ResultsTarget tissue doses of 0.009-0.4 μg SPIO/cm2 in lung led to an inflammatory response in the alveolar region characterized by interstitial inflammation and macrophage infiltration. In vitro, higher target tissue doses of ~1.2-4 μg SPIO/ cm2 of cells were required to induce transcriptional regulation of markers of inflammation, CXCL2 & CCL3, in C10 lung epithelial cells. Estimated in vivo macrophage SPIO nanoparticle doses ranged from 1-100 pg/cell, and induction of inflammatory markers was observed in vitro in macrophages at doses of 8-35 pg/cell.ConclusionsApplication of target tissue dosimetry revealed good correspondence between target cell doses triggering inflammatory processes in vitro and in vivo in the alveolar macrophage population, but not in the epithelial cells of the alveolar region. These findings demonstrate the potential for target tissue dosimetry to enable the more quantitative comparison of in vitro and in vivo systems and advance their use for hazard assessment and extrapolation to humans. The mildly inflammogentic cellular doses experienced by mice were similar to those calculated for humans exposed to the same material at the existing permissible exposure limit of 10 mg/m3 iron oxide (as Fe).Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-014-0046-4) contains supplementary material, which is available to authorized users.

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“…One interesting question is the dose comparison. In a study on iron oxide NPs, Teeguarden and co-workers concluded that when considering target tissue dosimetry, especially with a focus on macrophages, a good conformity between target cell doses triggering inflammatory processes in vitro (8-35 pg/cell) and in vivo (1-100 pg/cell) was observed [32].…”

Selection of potential iron oxide nanoparticles for breast cancer treatment based on in vitro cytotoxicity and cellular uptake

“…Models and methodologies for particle dosimetry that enables the determination of the dosage delivered to cells have already been presented, and it has been shown that usage of the cellular dose rather than administered dose improves the correlation between dose and response to particles in vitro and in vivo. [48][49][50][51] In addition to the impact of SPION-intrinsic properties, we found some strongly pronounced cell type-dependent differences affecting cellular SPION uptake. In our studies, we used 4 different breast cancer cell lines that strongly differ from each other concerning the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her2/ERBB2) and a cellular proliferation marker Ki-67.…”

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