Exposome and Exposure Modeling

PBPK of nanoparticles

(from Li et al., 2016)

About this project

Physiologically based pharmacokinetic (PBPK) modeling and characterizing the biodistribution of nanoparticles in the body.

People

Olivier Jolliet (ojolliet@umich.edu)

Dingsheng Li

Keywords

PBPK, intravenous administration, inhalation, phagocytosis, rats, cerium oxide, gold, titanium dioxide, polyacrylamide, polyethylene glycol coating

Project summary

Though the use of engineered nanoparticles has been exponentially increasing, little attention has been given to the nanoparticles biodistribution in the body. This project aims to establish a physiologically based pharmacokinetic (PBPK) model that accounts for nano-specific biobehaviors in order to understand the biodistribution of various types of nanoparticles.

The model has been first developed and tested on experimental data for polyethylene glycol-coated polyacrylamide (PAA-peg) nanoparticles intravenously injected to rats. By accounting for the phagocytosis process, the PBPK model successfully predicts the dynamics of PAA-peg nanoparticles between and within organs. According to the model, phagocytizing cells (PCs) quickly capture nanoparticles until saturation and constitute a major reservoir for nanoparticles. (Wenger et al., 2011, Li et al., 2014)

The PBPK framework was then adapted to address cerium oxide (CeO2) nanoparticles (Li et al., 2016, Fatouraie et al., 2016). A system of experimental apparatus is designed to integrate the generation, aging, and inhalation exposure of CeO2 nanoparticles to rats. The amounts found in organs are further analyzed with a mass balance approach to gain a holistic understanding of the biodistribution. The PBPK model is then slightly modified to accommodate unique phenomenon for inhaled nanoparticles including mucociliary clearance and entry into the systemic circulation by penetrating the alveolar wall. The recovered amount is predominantly in lungs and feces, with extrapulmonary organs contributing less than 2% in recovery rate. No differences in biodistribution patterns are found between fresh and aged CeO2 nanoparticles. The model predicts the biodistribution well and finds PCs in the pulmonary region are accountable for most of the nanoparticles not eliminated by feces.

To expand the model’s applicability, additional biodistribution data of nanoparticles collected from literatures are used for parameterization, including three polymers nanoparticles, three different sizes of silver nanoparticles, and one CeO2 nanoparticles (Li, 2015, chapter 4) as well as to gold and titanium dioxide nanoparticles (Carlander et al., 2016). Only parameters physiologically linked with the characteristics of nanoparticles are changed. Overall the model maintains its robustness by having a R2 of 0.69 – 0.97 between the log10 of measured and predicted results. The changes of certain parameters also offer insights on the relationship between nanoparticles’ characteristics and biodistribution.

In summary, this work highlights the importance of phagocytosis as a major determinant of nanoparticles biodistribution and provides a tool for better evaluating the human health risks posed by nanoparticles.

Figure 1. Predicted versus experimental LOg10 of concentration in different organs after exposure of rate to Nano CeO2 by inhalation (from Li et al., 2016).

Sub-project:

In vivo biodistribution and physiologically based pharmacokinetic modeling of inhaled fresh and aged cerium oxide nanoparticles

(Abstract taken from Li et al., 2016)

Background

Cerium oxide (CeO2) nanoparticles used as a diesel fuel additive can be emitted into the ambient air leading to human inhalation. Although biological studies have shown CeO2 nanoparticles can cause adverse health effects, the extent of the biodistribution of CeO2 nanoparticles through inhalation has not been well characterized. Furthermore, freshly emitted CeO2 nanoparticles can undergo an aging process by interaction with other ambient airborne pollutants that may influence the biodistribution after inhalation. Therefore, understanding the pharmacokinetic of newly-generated and atmospherically-aged CeO2 nanoparticles is needed to assess the risks to human health.

Methods

A novel experimental system was designed to integrate the generation, aging, and inhalation exposure of Sprague Dawley rats to combustion-generated CeO2 nanoparticles (25 and 90 nm bimodal distribution). Aging was done in a chamber representing typical ambient urban air conditions with UV lights. Following a single 4-hour nose-only exposure to freshly emitted or aged CeO2 for 15 min, 24 h, and 7 days, ICP-MS detection of Ce in the blood, lungs, gastrointestinal tract, liver, spleen, kidneys, heart, brain, olfactory bulb, urine, and feces were analyzed with a mass balance approach to gain an overarching understanding of the distribution. A physiologically based pharmacokinetic (PBPK) model that includes mucociliary clearance, phagocytosis, and entry into the systemic circulation by alveolar wall penetration was developed to predict the biodistribution kinetic of the inhaled CeO2 nanoparticles.

Results

Cerium was predominantly recovered in the lungs and feces, with extrapulmonary organs contributing less than 4 % to the recovery rate at 24 h post exposure. No significant differences in biodistribution patterns were found between fresh and aged CeO2 nanoparticles. The PBPK model predicted the biodistribution well and identified phagocytizing cells in the pulmonary region accountable for most of the nanoparticles not eliminated by feces.

Conclusions

The biodistribution of fresh and aged CeO2 nanoparticles followed the same patterns, with the highest amounts recovered in the feces and lungs. The slow decrease of nanoparticle concentrations in the lungs can be explained by clearance to the gastrointestinal tract and then to the feces. The PBPK model successfully predicted the kinetic of CeO2 nanoparticles in various organs measured in this study and suggested most of the nanoparticles were captured by phagocytizing cells.

Publications

Peer-reviewed journal articles

Li DS, Morishita M, Wagner JG, Fatouraie M, Wooldridge M, Eagle E, Barres J, Carlander U, Emond, Jolliet O, 2016. In vivo biodistribution and physiologically based pharmacokinetic modeling of inhaled fresh and aged cerium oxide nanoparticles. Particle and Fibre Toxicology, 13 (1) 45.
Fatouraie M, Eagle WE, Li DS, Morishita M, Barres J, Wagner JG, Jolliet O, Wooldridge MS, 2016. Combustion synthesis of CeO2 nanoparticles for aging and inhalation exposure studies. Journal of Aerosol Science, 106, 24-33.
Carlander U, Li DS, Jolliet O, Emond C, Johanson G, 2016. Towards a general physiologically based pharmacokinetic (PBPK) model for intravenously injected nanoparticles, International Journal of Nanomedicine, 11, 625–640.
Li DS, 2015. PhD Thesis. A Physiologically Based Pharmacokinetic Model Study of the Biological Fate, Transport and Behavior of Engineered Nanoparticles. (https://deepblue.lib.umich.edu/bitstream/handle/2027.42/111631/dingsli_1.pdf?sequence=1&isAllowed=y)
Li DS, Johanson G, Emond C, Carlander U, Philbert M and Jolliet O, 2014. Physiologically based pharmacokinetic modeling of polyethylene glycol-coated polyacrylamide nanoparticles in rats. Nanotoxicology, 8, Issue SUPPL. 1, 128-137.
Wenger Y, Schneider R.J., Reddy R, Kopelman R, Jolliet O and Philbert M.A, 2011. Tissue Distribution and Pharmacokinetics of Stable Polyacrylamide Nanoparticles Following Intravenous Injection in the Rat. Toxicology and Applied Pharmacology, 251 (3) 181-190.

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