Nanoparticles' health risks depend on their biodistribution in the body. Phagocytosis may greatly affect this distribution but has not yet explicitly accounted for in whole body pharmacokinetic models. Here, we present a physiologically based pharmacokinetic model that includes phagocytosis of nanoparticles to explore the biodistribution of intravenously injected polyethylene glycol-coated polyacrylamide nanoparticles in rats. The model explains 97% of the observed variation in nanoparticles amounts across organs. According to the model, phagocytizing cells quickly capture nanoparticles until their saturation and thereby constitute a major reservoir in richly perfused organs (spleen, liver, bone marrow, lungs, heart and kidneys), storing 83% of the nanoparticles found in these organs 120 h after injection. Key determinants of the nanoparticles biodistribution are the uptake capacities of phagocytizing cells in organs, the partitioning between tissue and blood, and the permeability between capillary blood and tissues. This framework can be extended to other types of nanoparticles by adapting these determinants.
To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NPdependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight.
Highlights Exposure to disinfecting chemicals is highly dependent on physicochemical property. Children are at elevated exposure due to more mouthing-mediated ingestion. Some disinfecting chemicals may pose health risks for certain modeled individuals. Estimated risks differ greatly between the uses of in vivo and in vitro toxicity endpoints.
Exposure to fine particulate matter (PM 2.5 ) is a major contributor to the global human disease burden. The indoor environment is of particular importance when considering the health effects associated with PM 2.5 exposures because people spend the majority of their time indoors and PM 2.5 exposures per unit mass emitted indoors are two to three orders of magnitude larger than exposures to outdoor emissions. Variability in indoor PM 2.5 intake fraction ( ), which is defined as the integrated cumulative intake of PM 2.5 per unit of emission, is driven by a combination of building-specific, human-specific, and pollutant-specific factors. Due to a limited availability of data characterizing these factors, however, indoor emissions and intake of PM 2.5are not commonly considered when evaluating the environmental performance of product life cycles. With the aim of addressing this barrier, a literature review was conducted and data characterizing factors influencing were compiled. In addition to providing data for the calculation of in various indoor environments and for a range geographic regions, this paper discusses remaining limitations to the incorporation of PM 2.5 -derived health impacts into life cycle assessments and makes recommendations regarding future research. Accepted ArticleThis article is protected by copyright. All rights reserved. Practical ImplicationsThis paper reviews and summarizes the factors that influence indoor inhalation intake fraction of fine particulate matter, with a focus on primary particle emissions indoors. It provides valuable data for the calculation of indoor inhalation intake fraction for a range of indoor environments and contributes to the effort to incorporate PM 2.5 -derived health impacts into life cycle assessment.
BackgroundCerium 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.MethodsA 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.ResultsCerium 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0156-2) contains supplementary material, which is available to authorized users.
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