BackgroundIndustrially produced quantities of TiO2 nanoparticles are steadily rising, leading to an increasing risk of inhalation exposure for both professionals and consumers. Particle inhalation can result in inflammatory and allergic responses, and there are concerns about other negative health effects from either acute or chronic low-dose exposure.ResultsTo study the fate of inhaled TiO2-NP, adult rats were exposed to 2-h intra-tracheal inhalations of V-48-radiolabeled, 20nm TiO2-NP aerosols (deposited NP-mass 1.40.5 mu g). At five time points (1h, 4h, 24h, 7d, 28d) post-exposure, a complete balance of the [V-48]TiO2-NP fate was quantified in organs, tissues, carcass, lavage and body fluids, including excretions.After fast mucociliary airway clearance (fractional range 0.16-0.31), long-term macrophage-mediated clearance (LT-MC) from the alveolar region is 2.6-fold higher after 28d (integral fraction 0.40 +/- 0.04) than translocation across the air-blood-barrier (integral fraction 0.15 +/- 0.01). A high NP fraction remains in the alveoli (0.44 +/- 0.05 after 28d), half of these on the alveolar epithelium and half in interstitial spaces. There is clearance from both retention sites at fractional rates (0.02-0.03 d(-1)) by LT-MC. Prior to LT-MC, [V-48]TiO2-NP are re-entrained to the epithelium as reported earlier for 20nm inhaled gold-NP (AuNP) and iridium-NP (IrNP).Conclusion Comparing the 28-day biokinetics patterns of three different inhaled NP materials TiO2-NP, AuNP and IrNP, the long-term kinetics of interstitial relocation and subsequent re-entrainment onto the lung-epithelium is similar for AuNP and Ir-NP but slower than for TiO2-NP. We discuss mechanisms and pathways of NP relocation and re-entrainment versus translocation. Additionally, after 28days the integral translocated fractions of TiO2-NP and IrNP across the air-blood-barrier (ABB) are similar and become 0.15 while the translocated AuNP fraction is only 0.04. While NP dissolution proved negligible, translocated TiO2-NP and IrNP are predominantly excreted in urine (0.1) while the urinary AuNP excretion amounts to a fraction of only 0.01. Urinary AuNP excretion is below 0.0001 during the first week but rises tenfold thereafter suggesting delayed disagglomeration. Of note, all three NP dissolve minimally, since no ionic radio-label release was detectable. These biokinetics data of inhaled, same-sized NP suggest significant time-dependent differences of the ABB translocation and subsequent fate in the organism.