Development of a PBPK-based health risk assessment framework for exposure to cerium, gold, silver and titanium engineered nanoparticles

Abstract

The study aim was to develop and implement a novel integrated approach for engineered nanoparticles risk assessment using several health risk assessment frameworks. The study managed to apply a physiologically based pharmacokinetic model for ceria nanoparticles to determine biokinetics of ceria nanoparticles, establish whether physiologically based pharmacokinetic models are a good risk assessment tool for ceria, gold, silver and titanium nanoparticles, identify physiological systems for potential cytotoxicity, genotoxicity, immunotoxic and metabolic effects and establish a novel risk assessment model framework.

The PBPK study showed that the biodistribution of ceria nanoparticles is largely dependent on the exposure route and dose. The time courses for various tissues for intravenously (IV) administered 5 nm ceria were well articulated by the model. Biokinetics of the liver and spleen were well articulated for 30 nm ceria whereas biokinetics for other tissues were not well articulated. There were challenges to re-optimise for inhalation, IT instillation, and oral exposure routes due to low absorption. PBPK models were proven to be good risk assessment tools to determine biokinetics of various types and sizes of nanoparticles as proven by the ceria, gold, silver and titanium nanoparticles PBPK models we studied. There was good correlations between predicted and observed values. The integration of PBPK models with AOPs and MOA helps with predicting the biokinetics of NPs and could further help predict the endpoint toxicities and the mechanisms and triggers behind the endpoint toxicities.

The toxicity of nanoparticles is influenced by size, dose concentration, coating and non-coating of nanoparticles and exposure duration. The literature review indicated that exposure to nanoparticles could lead to physiological disturbances resulting in disrupted homeostasis and adverse health effects. Both acute and chronic exposures could be toxic.

Lastly, a novel health risk assessment framework was constructed using integration of current health risk assessment framework and information integration framework. Framework integration allows mixed use of available health risk assessments frameworks, while information integration is the amalgamation of information from heterogeneous sources with differing conceptual, contextual and typographical representations. The health risk assessment framework will allow an integrated approach to conducting risk assessments using the latest available data and technologies. The advantage of this approach is time- and money-saving. The approach can be used to address any type of nanaoparticle exposure and route. The availability of scientific data is key to the implementation of the framework. The richer the information available the more robust the implementation of the framework will be.