Gastrointestinal Absorption and Toxicity of Nanoparticles and Microparticles: Myth, Reality and Pitfalls explored through Titanium Dioxide

Abstract

Daily oral exposure to vast numbers (>10¹³/adult/day) of micron or nano-sized persistent particles has become the norm for many populations. Significant airborne particle exposure is deleterious, so what about ingestion? Titanium dioxide in food grade form (fgTiO₂) , which is an additive to some foods, capsules, tablets and toothpaste, may provide clues. Certainly, exposed human populations accumulate these particles in specialised intestinal cells at the base of large lymphoid follicles (Peyer's patches) and it's likely that a degree of absorption goes beyond this- i.e. lymphatics to blood circulation to tissues. We critically review the evidence and pathways. Regarding potential adverse effects, our primary message, for today's state-of-art, is that in vivo models have not been good enough and at times woeful. We provide a 'caveats list' to improve approaches and experimentation and illustrate why studies on biomarkers of particle uptake, and lower gut/mesenteric lymph nodes as targets, should be prioritized.

Keywords: Peyer’s patch; absorption; gastrointestinal; nanoparticle; particle; titanium dioxide.

Figure 1. Detection of particle-loaded pigment cells using reflectance confocal microscopy.

(A) Section of human Peyer’s patch tissue (i.e. gut lymphoid follicle) with cell nuclei stained blue by Hoechst 33342 and imaged as a single 0.8 micron-thick optical slice with a confocal microscope. Regions are marked on for the intestinal lumen, follicle associated epithelium (FAE), sub-epithelial dome (SED) and base of the patch. At higher magnification (B and C), the laser reflectance signal reveals particle-loaded pigment cells, residing at the base of the Peyer’s patch. The fgTiO₂, which is a major contributor to this pigment [3] is highly reflective and provides a ready bio-marker for detection in tissue using light microscopy. Scale bars = 25 micron. These images are from a study approved by the UK NHS Health Research Authority, North West - Greater Manchester East Research Ethics Committee, REC reference 18/NW/0690.

Figure 2. Important considerations and caveats in absorption studies.

Murine models are frequently used to predict effects of oral particle exposure to humans but, mostly, these are flawed. Mimicking particle type is important whilst comparative cell loading (i.e. in the rodent model versus humans) may turn out to be the only reasonable, albeit technically demanding, approach for sensible quantitative dosing (1). If human cell exposure to oral particles is known, as it is for fgTiO₂ and some silicates [3], then any dosing matrix needs to allow some gut luminal release of such particles in an animal model (2). Gavage is stressful and its bolus doses are totally unlike general oral exposure to particles for humans. Moreover, such approaches encourage agglomeration and aggregation of particles (3). In addition, particles are sticky and adsorb to such dosing equipment (4). Finally, even if the issues of 1-4 are avoided, then analysis of particles in tissues must be very carefully validated as errors are frequent (5).