Identification of the appropriate dose metric for pulmonary inflammation of silver nanoparticles in an inhalation toxicity study

Abstract

A number of studies have shown that induction of pulmonary toxicity by nanoparticles of the same chemical composition depends on particle size, which is likely in part due to differences in lung deposition. Particle size mostly determines whether nanoparticles reach the alveoli, and where they might induce toxicity. For the risk assessment of nanomaterials, there is need for a suitable dose metric that accounts for differences in effects between different sized nanoparticles of the same chemical composition. The aim of the present study is to determine the most suitable dose metric to describe the effects of silver nanoparticles after short-term inhalation. Rats were exposed to different concentrations (ranging from 41 to 1105 µg silver/m³ air) of 18, 34, 60 and 160 nm silver particles for four consecutive days and sacrificed at 24 h and 7 days after exposure. We observed a concentration-dependent increase in pulmonary toxicity parameters like cell counts and pro-inflammatory cytokines in the bronchoalveolar lavage fluid. All results were analysed using the measured exposure concentrations in air, the measured internal dose in the lung and the estimated alveolar dose. In addition, we analysed the results based on mass, particle number and particle surface area. Our study indicates that using the particle surface area as a dose metric in the alveoli, the dose–response effects of the different silver particle sizes overlap for most pulmonary toxicity parameters. We conclude that the alveolar dose expressed as particle surface area is the most suitable dose metric to describe the toxicity of silver nanoparticles after inhalation.

• Dose metrics
• inhalation exposure
• nanotoxicology
• risk assessment

Acknowledgements

We would like to thank Ilse Gosens and John Boere for their help with the experimental design and Harry van Steeg for critical review of the manuscript. We thank Piet K. Beekhof for the analysis of the total protein, LDH and glutathione, and Henny W. Verharen, Hans J.C. Strootman, Ron F. Vlug, Christine M.R. Soputan, Jan Bos, Jolanda Rigters for their excellent technical assistance. In addition, we thank Jose van den Dungen for assistance with sample pretreatments and Chris T. W. M. Schneijdenberg for the assistance with the SEM imaging.

Declaration of interest

The authors declare that they have no competing interests.

This work was supported by the project “Integrated Risk Assessment of Nanomaterials” from the National Institute for Public Health and the Environment and by the NanoNextNL program “Risk Analysis and Technology Assessment: Human Health Risks”.

Supplementary material available online Supplementary Table S1 and Figures S1-S5