The kinetics of the tissue distribution of silver nanoparticles of different sizes

Abstract

Blood kinetics and tissue distribution of 20, 80 and 110 nm silver nanoparticles were investigated in rats up to 16 days after intravenous administration once daily for 5 consecutive days. Following both single and repeated injection, silver nanoparticles disappeared rapidly from the blood and distributed to all organs evaluated (liver, lungs, spleen, brain, heart, kidneys and testes) regardless of size. The 20 nm particles distributed mainly to liver, followed by kidneys and spleen, whereas the larger particles distributed mainly to spleen followed by liver and lung. In the other organs evaluated, no major differences between the sizes were observed. Size-dependent tissue distribution suggests size-dependent toxicity and health risks. Repeated administration resulted in accumulation in liver, lung and spleen, indicating that these organs may be potential target organs for toxicity after repeated exposure. A physiologically based pharmacokinetic (PBPK) model for nanoparticles which describes the kinetics of silver nanoparticles was developed. Model parameter values were estimated by fitting to data. No clear relation between parameter values and corresponding particle diameters became apparent.

Introduction

Silver nanoparticles are frequently used in consumer and medical products because of their effective antimicrobial activity [1], [2], [3], [4], [5]. Despite the rapidly growing share of silver-containing nanoproducts on the market [5], [6], [7], there is only limited information on the possible risks of exposure to silver nanoparticles. In a recent review evaluating the risk assessment of silver nanoparticles, different knowledge gaps were identified, including toxicokinetics [4]. Similar data gaps were identified for the possible registration of nanosilver as a substance under the EU REACH regulation [8].

The health risk is obviously related to the potential exposure of individuals to the nanomaterial. If there is no absorption, the potential risks are limited to possible local effects at the site of exposure mainly being lung, gastrointestinal tract, or skin. To date, almost all toxicological experiments dealing with nanoparticles describe the total inhaled, ingested, injected, or dermally applied dose of nanoparticles and do not investigate absorption or internal exposure. The internal exposure is that part of the external dose of nanoparticles that enters the systemic circulation and thus potentially reaches all organs and tissues.

Potential target organs for toxicity can be identified, by studying the distribution of nanoparticles over various organ systems preferably following intravenous administration. Oral, dermal and inhalation exposure to silver nanoparticles revealed distribution of these particles to several organs including liver, kidneys, lungs, heart, brain, testes, lymph nodes and skin [9], [10], [11], [12], [13], [14]. Depending on the route of administration, highest concentrations were found in stomach, liver, kidneys, lungs and skin.

When using intravenous administration, absorption is bypassed and other aspects of toxicokinetic processes, such as tissue distribution and elimination, can be studied with more precision. Differences in tissue distribution between single and repeated exposure provide insight into the potential of accumulation. Furthermore, information on the time required for elimination of nanoparticles from blood and tissues provides more detailed information about the potential accumulation after repeated exposure to nanoparticles.

So far, most studies on silver nanoparticles have described the distribution of only one size of particle [9], [10], [11], [12], [13], [14], [15], [16]. However, the size of nanoparticles can be a significant determinant of particle distribution as shown for gold nanoparticles by De Jong et al. [17] and for silica nanoparticles by Xie et al. [18]. In addition, information on similarities and differences in tissue distribution can aid in the discussion whether health risks differ between particles made of the same element but with different characteristics.

To obtain insight into the kinetic profile of silver nanoparticles, the aim of the present study was to determine the influence of particle size on tissue distribution and potential organ accumulation of silver nanoparticles in the rat. Rats were exposed to various sizes of silver nanoparticles (20, 80 and 110 nm) by intravenous administration once daily for 5 consecutive days. Blood kinetics and tissue distribution of silver nanoparticles were investigated up to 16 days after intravenous exposure. In order to describe the kinetics of silver nanoparticles, a physiologically based pharmacokinetic (PBPK) model was developed that fits the concentration-time course in blood, liver, spleen and kidney simultaneously. This mathematical model can be used to identify potential target organs relevant for risk assessment, and estimate levels of silver nanoparticles in several tissues after different exposure scenarios. Moreover, it can aid in the design of optimal sampling schemes and possibly in gaining insight between the kinetics of nanoparticles and their diameter.