Article

Blood levels of titanium before and after oral administration of titanium dioxide

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Abstract

The normal titanium levels in the blood of males between 24 and 66 years of age were found to be 11.2 mug/l (rsd 4.1). After oral administration of titanium dioxide containing capsules or as powder (anatas) it could be observed that the material can be absorbed from the gastro-intestinal tract. If two titanium dioxide qualities, having different mean particle sizes (0.16 mum and 0.38 mum), are administered orally, the latter shows less absorption, most likely due to agglomeration phenomena, The blood concentration/time correlation shows the type of curves which are characteristic for a persorption mechanism of absorption and reveal a high individual fluctuation. An increase of the administered dose by twice the amount shows only a tendentious response in the corresponding blood levels. The method of analysis was ICP-AES. A pretreatment of the samples in order to eliminate the organic matrix is necessary.

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... Oral absorption of particulate titanium dioxide (TiO 2 ), a common food additive and excipient used in nutraceuticals, pharmaceuticals and toothpaste [10], has been especially well studied in animals [11], but barely so in man. To date, only Bockmann et al. have shown in humans that measurable increases in total titanium (Ti) levels occur in the blood stream following ingestion of capsules containing TiO 2 particles [12]. Given that TiO 2 is so resistant to dissolution, and that it accumulates in human intestinal cells [3][4][5], it is probable that Bockmann et al. were showing direct particle uptake, although this was not measured. ...
... Given that TiO 2 is so resistant to dissolution, and that it accumulates in human intestinal cells [3][4][5], it is probable that Bockmann et al. were showing direct particle uptake, although this was not measured. Despite high interest on the use of TiO 2 particles and their potential impact following acute and chronic exposure, investigative studies looking at TiO 2 absorption in humans have only been reported once, in 2015 [13], since the initial published findings in the year 2000 [12]. However, in the recent work, high baseline values appear to have prevented observations on the appearance of Ti in the circulation following ingestion of TiO 2 [13]. ...
... Our current findings substantiate those of Bockmann et al., in which a comparable trial design demonstrated a similar pattern of titanium loading into the blood stream of human subjects following the ingestion of TiO 2 [12]. However, we now show that these total Ti signals by ICP can be reasonably attributed to the actual absorption of whole particles (i.e. ...
Article
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Exposure to persistent engineered nano and micro particles via the oral route is well established. Animal studies have demonstrated that, once ingested, a small proportion of such particles translocate from the gastrointestinal tract to other tissues. Exposure to titanium dioxide is widespread via the oral route, but only one study has provided indirect evidence (total titanium analyses) of absorption into the blood stream in humans. We sought to replicate these observations and to provide additional evidence for particulate uptake. Human volunteers with normal intestinal permeability were orally administered 100 mg pharmaceutical/food grade titanium dioxide. Blood samples were collected from 0.5 to 10 h post ingestion and analysed for the presence of reflectant bodies (particles) by dark field microscopy, and for total titanium by inductively coupled plasma mass spectrometry (ICP-MS). Blood film analyses implied early absorption of particles (2 h) with a peak maximum at 6 h following ingestion. The presence of these reflectant particles in blood roughly mirrored the levels of total titanium by ICP-MS, providing good evidence for the latter being a measure of whole particle (titanium dioxide) absorption. This study shows that a fraction of pharmaceutical/food grade titanium dioxide is absorbed systemically by humans following ingestion. It confirms that at least two routes of particle uptake may exist in the human gut- one proximal and one distal. Further work should quantify human exposure and uptake of such persistent particles.
... The amount of TiO 2 that gets absorbed by the body is actually extremely low (Cho et al., 2013;Jovanović, 2015). This was first proved by detecting up to 43.2 ± 4.6 μg/L of TiO 2 in the blood of volunteers after oral ingestion of 22.9 mg of TiO 2 incorporated in gelatin capsules (Böckmann, Lahl, et al., 2000). If the ingested amount had totally crossed the intestinal barrier, the amount for an adult with 6 L of blood would amount to 3.8 mg/L, i.e. roughly 100 times more than the amount found in reality, which confirms the low absorption rate. ...
... The discrepancy can be explained by the time of tests, the formulation, and the type of particles. First, the collection of human blood samples in the study of Jones et al. (2015) was performed 2, 4, 24 and 48 h after dosing while peak level of TiO 2 was noted between 4 and 12 h for all volunteers in the study of Böckmann et al. (2000). Second, levels in blood depend on type of formulation (TiO 2 encapsulated in gelatin capsules or not; Böckmann et al., 2000). ...
... First, the collection of human blood samples in the study of Jones et al. (2015) was performed 2, 4, 24 and 48 h after dosing while peak level of TiO 2 was noted between 4 and 12 h for all volunteers in the study of Böckmann et al. (2000). Second, levels in blood depend on type of formulation (TiO 2 encapsulated in gelatin capsules or not; Böckmann et al., 2000). Third, the particles used in these two studies were different from a physical-chemical point of view, which may modify particle reactivity, agglomeration and the pathway/kinetics used to cross the physiological barriers. ...
Article
In the past decades, research into nanoscience and nanotechnologies has grown explosively and stimulated a large panel of scientific and technological fields. The boosting effect comes from either the reinvestigation of scientific fields by considering the nanoscale as a relevant level for improving our knowledge or from the extraordinary development of new tools that have democratized access to the nanoscale, such as AFM which is now a routine tool in most labs. This stimulating research has also reached the field of food science and biobased products. The INRA's Science for Food & Bioproducts Engineering division ('CEPIA') has been engaged in this huge challenge, and selected results are presented here.
... They were screened for a high fluorescent yield and the excitation-emission constraints of typical research and medical microscopy systems (22,27,33). Following the initial success of the uptake of nanoparticles (5,15), further development emphasised the shift of the excitation range to a highly penetrative infrared and the optimisation of fluorescence intensity. Nevertheless, the controversies over the route of application of nanocrystals, as well as the mechanism of their absorption and biodistribution remain. ...
... Our study was prompted by discrepancies in the literature with regard to the penetration properties of various nanoparticles and their distribution pattern in the organism (1,5,7,10,16,19,24,26). We focused on establishing whether the size and shape of nanocrystals affects their bioavailability and distribution kinetics after alimentary application. ...
... Most of their studies were conducted with the intravenous (IV) application of nanocrystaline substances (1,6,10,16,19,26). In a few instances in which the alimentary uptake was reported, the authors only noted the appearance of the applied substances in blood (5,24). Examples of a few thoroughly considered experiments were presented by Baek et al (3) and by Hillyer and Albrecht (15). ...
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Luminescent nanocrystals and quantum dots show great potential for use as fluorescent markers in biology and medicine. Preliminary results have been encouraging and show the visualising properties of quantum dots in the diagnosis of tumours (1, 6, 10, 31). However, the first generations of nanocrystals were based on a heavy-metal core, which was un-stable and shed heavy-metal ions into biological me-dia (8). This, coupled with a lack of information on their biodistribution and pharmacokinetics, rendered them unusable for purposes outside research. Thus the search started for a non-heavy metal solution for highly fluorescent nanocrystals. Recently developed rare-earth-doped nanocrystals are a promising material
... Studies in humans on orally administrated TiO 2 showed a low bioavailability [68][69][70]. Basal titanium blood levels ranged between 5.9-18.1 µg/L (mean 11.1 µg/L) and peaked after 8-12 h at 37.4-49.7 µg/L after ingestion of 22.9 mg TiO 2 in a gelatin capsule. Administration of 380 nm sized TiO 2 (anatase) showed lower absorption than 160 nm sized TiO 2 (anatase). ...
... Administration of 380 nm sized TiO 2 (anatase) showed lower absorption than 160 nm sized TiO 2 (anatase). The highest titanium blood concentration was detected at 109.9 µg/L, after the ingestion of 45.8 mg TiO 2 in a gelatin capsule, after 8 h, showing large differences in absorption among the group of six male volunteers [68]. The ingestion of 100 mg food-grade TiO 2 (E171) increased total titanium blood levels after 6-8 h, with peak titanium blood concentrations reaching 10 ppb in comparison to 1.5 ppb basal levels [70]. ...
... Except for a limited number of oral absorption experiments and the observation of increased blood TiO 2 levels in UC patients from a Swiss IBD cohort. Yet no associations between E171 exposure and the induction inflammatory responses, alteration of gut microbiota, and colon cancer have been reported in humans [68][69][70]89]. ...
Article
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Titanium dioxide (TiO2) is used as a food additive (E171) and can be found in sauces, icings, and chewing gums, as well as in personal care products such as toothpaste and pharmaceutical tablets. Along with the ubiquitous presence of TiO2 and recent insights into its potentially hazardous properties, there are concerns about its application in commercially available products. Especially the nano-sized particle fraction (<100 nm) of TiO2 warrants a more detailed evaluation of potential adverse health effects after ingestion. A workshop organized by the Dutch Office for Risk Assessment and Research (BuRO) identified uncertainties and knowledge gaps regarding the gastrointestinal absorption of TiO2, its distribution, the potential for accumulation, and induction of adverse health effects such as inflammation, DNA damage, and tumor promotion. This review aims to identify and evaluate recent toxicological studies on food-grade TiO2 and nano-sized TiO2 in ex-vivo, in-vitro, and in-vivo experiments along the gastrointestinal route, and to postulate an Adverse Outcome Pathway (AOP) following ingestion. Additionally, this review summarizes recommendations and outcomes of the expert meeting held by the BuRO in 2018, in order to contribute to the hazard identification and risk assessment process of ingested TiO2.
... Translocation across biological barriers (lung, skin, intestine) depends on the crystal form (anatase or rutile), coating, size, surface area and aggregate/agglomerate formation [3]. A systemic passage for TiO 2 is documented in human [4][5][6] and resembles that reported in rodents [7,8], with accumulation in the liver and spleen of nano-and submicronic particles [9], indicating a low but chronic distribution of TiO 2 particulate matter in the human organism. In vivo studies in rodents exposed to TiO 2 reported toxic effects such as inflammation, impairment of biological barrier functions (intestinal, placental, bloodtestis), as well as the promotion of cancer development [7,10,11]. ...
... Similar observations have been reported by other groups after 6 h of perfusion with TiO 2 -NPs models, with Ti signals in the range of the background levels of the control perfusion medium [34,35], as herein reported. In these studies, including the present, the TiO 2 concentration used for perfusion (10 to 25 μg/mL for toxicokinetic purposes) was approximately 1000 times higher than the basal Ti blood level in humans (10 μg/L) [4,5] in order to optimize particle detection under a short time of perfusion (i.e., maximum 6 h) and given the short viability of the placenta ex vivo in a non-recirculating system. A high TiO 2 concentration in perfusion medium could rapidly lead to clogging of the intervillous space on the maternal side, limiting particle recovery on the foetal side. ...
Article
Full-text available
Background: Titanium dioxide (TiO2) is broadly used in common consumer goods, including as a food additive (E171 in Europe) for colouring and opacifying properties. The E171 additive contains TiO2 nanoparticles (NPs), part of them being absorbed in the intestine and accumulated in several systemic organs. Exposure to TiO2-NPs in rodents during pregnancy resulted in alteration of placental functions and a materno-foetal transfer of NPs, both with toxic effects on the foetus. However, no human data are available for pregnant women exposed to food-grade TiO2-NPs and their potential transfer to the foetus. In this study, human placentae collected at term from normal pregnancies and meconium (the first stool of newborns) from unpaired mothers/children were analysed using inductively coupled plasma mass spectrometry (ICP-MS) and scanning transmission electron microscopy (STEM) coupled to energy-dispersive X-ray (EDX) spectroscopy for their titanium (Ti) contents and for analysis of TiO2 particle deposition, respectively. Using an ex vivo placenta perfusion model, we also assessed the transplacental passage of food-grade TiO2 particles. Results: By ICP-MS analysis, we evidenced the presence of Ti in all placentae (basal level ranging from 0.01 to 0.48 mg/kg of tissue) and in 50% of the meconium samples (0.02-1.50 mg/kg), suggesting a materno-foetal passage of Ti. STEM-EDX observation of the placental tissues confirmed the presence of TiO2-NPs in addition to iron (Fe), tin (Sn), aluminium (Al) and silicon (Si) as mixed or isolated particle deposits. TiO2 particles, as well as Si, Al, Fe and zinc (Zn) particles were also recovered in the meconium. In placenta perfusion experiments, confocal imaging and SEM-EDX analysis of foetal exudate confirmed a low transfer of food-grade TiO2 particles to the foetal side, which was barely quantifiable by ICP-MS. Diameter measurements showed that 70 to 100% of the TiO2 particles recovered in the foetal exudate were nanosized. Conclusions: Altogether, these results show a materno-foetal transfer of TiO2 particles during pregnancy, with food-grade TiO2 as a potential source for foetal exposure to NPs. These data emphasize the need for risk assessment of chronic exposure to TiO2-NPs during pregnancy.
... Most of the orally administered titanium dioxide (97%) is unabsorbed and excreted in the feces (Jin and Berlin, 2015;Schroeder et al., 1963). Bockmann et al. (2000) found measurable increases in blood titanium following oral ingestion of 22.9 or 45.8 mg titanium dioxide capsules. Following a single 22.9 mg dose, peak blood levels of 43.2 ± 4.52 μg/L (n = 5) were observed between 4 and 12 h postdosing, with a minor peak at 0.25-1 h. ...
... The study reaffirmed that a small fraction of titanium dioxide is absorbed systemically by humans following oral ingestion, with a peak blood titanium level of 11 ppb observed at 6 h post-ingestion. These findings are consistent with those of Bockmann et al. (2000). ...
Article
Full-text available
Biomonitoring equivalents (BEs) have been increasingly applied for biomonitoring purposes by regulatory bodies worldwide. The present report describes the development of a BE for titanium based on a 4-step process: (i) identification of a critical study/point of departure (PoD) supporting an established oral exposure guidance value (OEGV);, (ii) review the available oral PK data and application of a pharmacokinetic model for titanium; (iii) selection of the most appropriate biomarker of exposure in a specific tissue and calculation of steady-state tissue levels corresponding to the PoD in the critical study; and (iv) derivation of BE value adjusting for the uncertainties considered in the original OEGV assessment. Using the above 4-step approach, a blood BE value of 32.5 μg titanium/L was derived. Key components of the analysis included a pharmacokinetic model developed by investigators at the Netherlands National Institute of Public Health (RIVM) and a two-year rodent bioassay of titanium conducted by the US National Cancer Institute. The most sensitive pharmacokinetic parameter involved in the current BE derivation is the oral absorption factor of 0.02%. The provisional BE proposed in this article may be updated as new information on the pharmacokinetics of titanium becomes available.
... fluid [32] initially by a process known as persorp-Volkheimer with his co-workers, in a series of tion. In addition these were the first studies conarticles from 1965, was the main proponent of this ducted in human volunteers, which has only been field that led LeFevre and colleagues (reviewed in repeated on a few occasions with 2-mm radiolabelled Ref. [28]) to investigate the PP accumulation of polystyrene microspheres, titanium dioxide, and insmaller micron-sized particles in a series of chronic testinal contrast media, respectively [33][34][35][36][37]. feeding experiments using mice some 25 years ago. ...
... Further the useful upper limit of particulate absorption of therapeutic drug delivery carriers and coupled atomic emission spectroscopy of withdrawn the ability to redirect particulates to GIT regions blood suggests that 160-nm titanium oxide particles mediating lymphatic absorption has yet to be de-are absorbed more effectively than 380-nm sized termined. The effects of mucus turnover and epitheli-particulates following administration to human vol-6 al sloughing, estimated to be 287 g / daily or 50 3 10 unteers [34]. This is in agreement with in vivo cells / min in man, cannot be ignored, particularly studies performed in rats in our laboratories [69]. ...
... Titania has also been linked to Crohn disease from gastrointestinal intake and it has been classified as a possible carcinogen ( (Lomer et al. 2000(Lomer et al. , 2001(Lomer et al. , 2002(Lomer et al. , 2004(Lomer et al. , 2005Powell et al. 2000Powell et al. , 2010. Based on the literature, TiO 2 has clear potential for absorption by mammals as well as for storage in various organs after ingestion where it can cause tissue damage and alter biochemical parameters (Huggins and Froehlich 1966;Filho et al. 1991;Jani et al. 1994;Böckmann et al. 2000;Olmedo et al. 2003Olmedo et al. , 2008Wang et al. 2007;Fabian et al. 2008;Sugibayashi et al. 2008;Liu et al. 2009;Duan et al. 2010;Hu et al. 2010;Cui et al. 2011;Xie et al. 2011;Nogueira et al. 2012;Umbreit et al. 2012;Sang et al. 2013a,b;Shinohara et al. 2014;Tassinari et al. 2014). TiO 2 has also been indicated as an immunotoxin in vertebrates Jovanovic and Palic 2012;Sang et al. 2012Sang et al. , 2013a. ...
... TiO 2 has also been indicated as an immunotoxin in vertebrates Jovanovic and Palic 2012;Sang et al. 2012Sang et al. , 2013a. Böckmann et al. (2000) observed a 5 to 10 times increase of TiO 2 levels in blood when humans are ingested with capsules containing 23 or 46 mg. Smaller TiO 2 particles were absorbed by the gastrointestinal tract at a better rate than larger ones. ...
Book
While nutraceuticals were verified to be expedient, they often lack stability, bioavailability, and permeability, and nano-nutraceuticals are being developed to afford a solution to the problem. Nanotechnology in Nutraceuticals: Production to Consumption delves into the promises and prospects of the application of nanotechnology to nutraceuticals, addressing concepts, techniques, and production methods. Nutraceuticals retain less stability, efficacy, and bioavailability when entering the human body. To overcome such problems, nanotechnology shows promise when applied as a tool to improve the quality and stability of nutraceuticals. This book discusses metallic nanoparticles and their applications in the food industry with specific application to nutraceuticals. It includes detailed discussion on potential functional properties of nutraceuticals with regard to antimicrobial activity, anti-inflammatory activity, and anti-cancer activity. Since nanoparticles can be toxic past a certain limit, implementing nanotechnology under thoughtful regulations is considered critical. The book addresses these issues with chapters covering the principles for the oversight of nanotechnologies and nanomaterials in nutraceuticals, the implications of regulatory requirements, the ethics and economics of nano-nutraceuticals, and consumer acceptance of nanotechnology based foods.
... Uptake of TiO 2 particles by the gut has been studied in animals, but rarely in humans (Jovanovic 2015). The only human volunteer studies conducted with single dose administration suggest that the oral bioavailability of TiO 2 is low (Pele et al. 2015;B€ ockmann et al. 2000;Jones et al. 2015). It should be noted that low oral uptake of nanomaterials can still lead to high organ burdens when there is long-term, frequent exposure in combination with low excretion or high persistence. ...
... mg Ti/kg body weight/day and since TiO 2 is highly stable, it is not likely degraded (dissolved) in the intestine and therefore mostly defecated (Weir et al. 2012;Rompelberg et al. 2016;Sohal et al. 2018). Human volunteer studies indicate that the oral bioavailability of TiO 2 is low, but accumulation in tissues may occur in time (Pele et al. 2015;B€ ockmann et al. 2000). While inhalation may be the primary route for TiO 2 exposure in the workplace, in non-occupational settings Ti concentrations in air are very low, in the range of 0.01-0.1 lg/m 3 , resulting in a maximum exposure through inhalation of only 1 lg Ti/day (WHO 1982). ...
Article
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Silicon dioxide (silica, SiO2, SAS) and titanium dioxide (TiO2) are produced in high volumes and applied in many consumer and food products. As a consequence, there is a potential human exposure and subsequent systemic uptake of these particles. In this study we show the characterization and quantification of both total silicon (Si) and titanium (Ti), and particulate SiO2 and TiO2 in postmortem tissue samples from 15 deceased persons. Included tissues are liver, spleen, kidney and the intestinal tissues jejunum and ileum. Low-level analysis was enabled by the use of fully validated sample digestion methods combined with (single particle) inductively coupled plasma high resolution mass spectrometry techniques (spICP-HRMS). The results show a total-Si concentration ranging from <2 to 191 mg Si/kg (median values of 5.8 (liver), 9.5 (spleen), 7.7 (kidney), 6.8 (jejunum), 7.6 (ileum) mg Si/kg) while the particulate SiO2 ranged from <0.2 to 25 mg Si/kg (median values of 0.4 (liver), 1.0 (spleen), 0.4 (kidney), 0.7 (jejunum, 0.6 (ileum) mg Si/kg), explaining about 10% of the total-Si concentration. Particle sizes ranged from 150 to 850 nm with a mode of 270 nm. For total-Ti the results show concentrations ranging from <0.01 to 2.0 mg Ti/kg (median values of 0.02 (liver), 0.04 (spleen), 0.05 (kidney), 0.13 (jejunum), 0.26 (ileum) mg Ti/kg) while particulate TiO2 concentrations ranged from 0.01 to 1.8 mg Ti/kg (median values of 0.02 (liver), 0.02 (spleen), 0.03 (kidney), 0.08 (jejunum), 0.25 (ileum) mg Ti/kg). In general, the particulate TiO2 explained 80% of the total-Ti concentration. This indicates that most Ti in these organ tissues is particulate material. The detected particles comprise primary particles, aggregates and agglomerates, and were in the range of 50–500 nm with a mode in the range of 100–160 nm. About 17% of the detected TiO2 particles had a size <100 nm. The presence of SiO2 and TiO2 particles in liver tissue was confirmed by scanning electron microscopy with energy dispersive X-ray spectrometry.
... A study on seven male subjects using TiO 2 anatase particles with a mean size of 160 nm and 380 nm showed that the particles were partially absorbed by the human gut leading to peak titanium levels in blood between 4 and 12 hours post oral ingestion (Bockmann et al., 2000;Pele et al., 2015). The insolubility of TiO 2 suggests particle uptake. ...
... It may even be due to "reach out" of intestinal dendritic cells, sampling directly from the lumen. Once having passed the epithelial barrier, [ 48 V]TiO 2 NP may then move from the gut to the "body" most likely via the lymphatic network, either as particles alone or within migrating phagocytic cells (Bockmann et al., 2000;Pele et al., 2015). ...
Article
The biokinetics of a size-selected fraction (70nm median size) of commercially available and ⁴⁸V-radiolabeled [⁴⁸V]TiO2 nanoparticles has been investigated in female Wistar-Kyoto rats at retention timepoints 1h, 4h, 24h and 7days after oral application of a single dose of an aqueous [⁴⁸V]TiO2-nanoparticle suspension by intra-esophageal instillation. A completely balanced quantitative body clearance and biokinetics in all organs and tissues was obtained by applying typical [⁴⁸V]TiO2-nanoparticle doses in the range of 30–80 μg•kg⁻¹ bodyweight, making use of the high sensitivity of the radiotracer technique. The [⁴⁸V]TiO2-nanoparticle content was corrected for nanoparticles in the residual blood retained in organs and tissue after exsanguination and for ⁴⁸V-ions not bound to TiO2-nanoparticles. Beyond predominant fecal excretion about 0.6% of the administered dose passed the gastro-intestinal-barrier after -h and about 0.05% were still distributed in the body at day-7, with quantifiable [⁴⁸V]TiO2-nanoparticle organ concentrations present in liver (0.09ng•g⁻¹), lungs (0.10ng•g⁻¹), kidneys (0.29ng•g⁻¹), brain (0.36ng•g⁻¹), spleen (0.45ng•g⁻¹), uterus (0.55ng•g⁻¹) and skeleton (0.98ng•g⁻¹). Since chronic, oral uptake of TiO2 particles (including a nano-fraction) by consumers has continuously increased in the past decades, the possibility of chronic accumulation of such biopersistent nanoparticles in secondary organs and the skeleton raises questions about the responsiveness of their defense capacities, and whether these could be leading to adverse health effects in the population at large. After normalizing the fractions of retained [⁴⁸V]TiO2-nanoparticles to the fraction that passed the gastro-intestinal-barrier and reached systemic circulation the biokinetics was compared to the biokinetics determined after IV-injection (Part 1). Since the biokinetics patterns differ largely IV-injection is not an adequate surrogate for assessing the biokinetics after oral exposure to TiO2 nanoparticles.
... The mechanisms suggested by the TiO 2 and SiO 2 data include a combination of transcellular transport of intact particles via phagocytosis through M-cells of Peyer's patches, transcellular and paracellular transport of disintegrated molecules released from the particle surface, paracellular transport of the intact particles between damaged epithelial cells, and persorption of intact particles through dead epithelial cells. 50,53,54 As research progresses, data on the full range of novel chemical entities that may be proposed for use in food will emerge. ...
... Therefore it is important to consider how such inter-individual differences may affect the stability and movement of orally administered substances. 53 The age of an individual can affect a variety of factors such as the pH at each point of the GI tract, the transit time of fluids, and the barrier function of the lining. In infants, permeability is significantly higher than in the average adult. ...
Article
Full-text available
Many natural chemicals in food are in the nanometer size range, and the selective uptake of nutrients with nanoscale dimensions by the gastrointestinal (GI) tract is a normal physiological process. Novel engineered nanomaterials (NMs) can bring various benefits to food, e.g., enhancing nutrition. Assessing potential risks requires an understanding of the stability of these entities in the GI lumen, and an understanding of whether or not they can be absorbed and thus become systemically available. Data are emerging on the mammalian in vivo absorption of engineered NMs composed of chemicals with a range of properties, including metal, mineral, biochemical macromolecules, and lipid‐based entities. In vitro and in silico fluid incubation data has also provided some evidence of changes in particle stability, aggregation, and surface properties following interaction with luminal factors present in the GI tract. The variables include physical forces, osmotic concentration, pH, digestive enzymes, other food, and endogenous biochemicals, and commensal microbes. Further research is required to fill remaining data gaps on the effects of these parameters on NM integrity, physicochemical properties, and GI absorption. Knowledge of the most influential luminal parameters will be essential when developing models of the GI tract to quantify the percent absorption of food‐relevant engineered NMs for risk assessment. WIREs Nanomed Nanobiotechnol 2015, 7:609–622. doi: 10.1002/wnan.1333 For further resources related to this article, please visit the WIREs website.
... An absorption study (Böckmann et al. 2000) determined that humans orally ingesting TiO2 in capsules containing 23 or 46 mg showed a 5 to 10 times increase of TiO2 levels in the blood. TiO2 was absorbed by the GIT in a size dependent manner, where small particles were absorbed at a better rate than larger ones. ...
... Based on findings from various studies on mammals, it appears that titanium dioxide fails to satisfy the two conditions on which the JECFA (1969) assessment was based: lack of absorption and lack of accumulation in body tissue. Based on the literature, titanium dioxide has clear potential for absorption by mammals after ingestion or injection, as well as for storage in various organs (Huggins and Froehlich 1966;Filho et al. 1991;Jani et al. 1994;Böckmann et al. 2000;Olmedo et al. 2003;Wang et al. 2007;Fabian et al. 2008;Olmedo et al. 2008;Sugibayashi et al. 2008;Liu et al. 2009;Duan et al. 2010;Hu et al. 2010;Cui et al. 2011;Xie et al. 2011;Nogueira et al. 2012;Umbreit et al. 2012;Sang, Fei, et al. 2013;Sang, Li, et al. 2013;Shinohara et al. 2014;Tassinari et al. 2014), where it can cause tissue damage and alter biochemical parameters. These properties, however, are most likely dependent on the concentration and size of TiO2 particles. ...
Thesis
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Titanium dioxide nanoparticles (TiO2) have the potential to cause adverse effects on the health of aquatic animals and humans, but the understanding of the underlying mechanisms is limited. Major task of this thesis was to connect gaps in the current knowledge of TiO2 toxicology and mode of action with a comprehensive research including molecular, cellular, organismal, and ecosystem responses toward environmentally relevant concentrations TiO2 in a variety of tests organisms or in situ aquatic ecosystems. The research was divided into following steps: 1) Assess current governmental legislations regarding the usage and safety of TiO2 as an human food additive and evaluate the need for toxicological reassessment; 2) Perform series of specifically targeted toxicology experiments on standard model species of interest (freshwater, marine, and terrestrial organisms); 3) Reevaluate the standard exposure methodology in terms of light conditions; 4) Perform a higher tier toxicity tests such as community structure analysis and in situ outdoor mesocosms tests in order to determine the impact level of TiO2 on the whole aquatic ecosystem. The main results of this thesis are: 1) There is a disagreement with the 1969 decision to approve the use of TiO2 as an inactive ingredient in human food without an established acceptable daily intake, stating that neither significant absorption nor tissue storage following ingestion of TiO2 was possible; 2) TiO2 exposure is causing premature hatching in freshwater fish, is delaying pupation and hatching in fruit flies, and is causing a stress to marine corals, however these effects occur at concentrations higher than environmentally relevant concentrations; 3) Exposure to environmental estimated concentration of nano-TiO2 significantly increased fish mortality during Aeromonas hydrophila and Edwardsiella ictaluri challenge by modulating fish immune responses and interfering with resistance to bacterial pathogens, thus having the potential to affect fish survival in a disease outbreak; 4) The first semi-quantitative histopathology scoring system of fish exposed to nanoparticles was presented and tested; 5) It was concluded that TiO2 is phototoxic and that especially order Cladocera appeared to be very sensitive and prone to TiO2 phototoxicity; 6) Environmentally relevant concentration of TiO2 can affect up to 39 % of the macroinvertebrate community structure; and finally 7) Environmentally relevant concentrations of TiO2 nanoparticles may negatively affect certain parameters and taxa of the freshwater lentic aquatic ecosystem, however, these negative effects are not big enough to affect the overall function of the ecosystem, as there were no cascade effects leading to a major change in its trophic state or primary production.
... Studies in adult human subjects highlight a low but detectable oral bioavailability. Male volunteers ingested anatase particles at doses of 23 and 46 mg in gelatin capsules (mean particle size of 160 nm) or as a powder (mean particle size of 380 nm) [70]. Pretreatment blood Ti levels, measured by ICP-atomic emission spectroscopy, ranged between 0.007 and 0.02 µg/ml. ...
... A peak Ti blood concentration of ~ 10 µg/ml (against a background of ~ 1.5 µg/ml) was detected at 6 h after ingestion of the test item. Thus, this report presented by Pele et al. [72] not only confirms the earlier finding of Böckmann et al. [70] in revealing a peak of Ti in the blood after oral intake of TiO 2 , but also demonstrates that at least part of this Ti appears in the blood as whole particles. There is an intriguing difference between the background Ti concentration of whole blood in most rodent studies (0.05 µg/ml or higher) and the lower levels observed in human blood (0.007-0.02 µg/ ml). ...
Article
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Nanomaterial engineering provides an important technological advance that offers substantial benefits for applications not only in the production and processing, but also in the packaging and storage of food. An expanding commercialization of nanomaterials as part of the modern diet will substantially increase their oral intake worldwide. While the risk of particle inhalation received much attention, gaps of knowledge exist regarding possible adverse health effects due to gastrointestinal exposure. This problem is highlighted by pigment-grade titanium dioxide (TiO2), which confers a white color and increased opacity with an optimal particle diameter of 200-300 nm. However, size distribution analyses showed that batches of food-grade TiO2 always comprise a nano-sized fraction as inevitable byproduct of the manufacturing processes. Submicron-sized TiO2 particles, in Europe listed as E 171, are widely used as a food additive although the relevant risk assessment has never been satisfactorily completed. For example, it is not possible to derive a safe daily intake of TiO2 from the available long-term feeding studies in rodents. Also, the use of TiO2 particles in the food sector leads to highest exposures in children, but only few studies address the vulnerability of this particular age group. Extrapolation of animal studies to humans is also problematic due to knowledge gaps as to local gastrointestinal effects of TiO2 particles, primarily on the mucosa and the gut-associated lymphoid system. Tissue distributions after oral administration of TiO2 differ from other exposure routes, thus limiting the relevance of data obtained from inhalation or parenteral injections. Such difficulties and uncertainties emerging in the retrospective assessment of TiO2 particles exemplify the need for a fit-to-purpose data requirement for the future evaluation of novel nano-sized or submicron-sized particles added deliberately to food.
... No acceptable daily intake (ADI) for oral ingestion of TiO 2 has been derived in the past due to the absence of observed toxic effects in the available chronic rodent study [4], the generally assumed negligible uptake of TiO 2 following ingestion [5], and the assumed insolubility and inertness of the material [6,7]. Recent human volunteer studies, however, show elevated blood Ti levels (and indications of TiO 2 particles) 6 h after ingestion of food grade TiO 2 [8], confirming earlier reports of increased blood Ti-levels after ingestion of 160 nm and 380 nm TiO 2 particles [9]. Upon evaluating food grade TiO 2 , the European Food Safety Agency (EFSA) acknowledged that TiO 2 is absorbed after oral application, albeit to a low extent, and transported to various organs [10]. ...
... Probably, most human subjects followed a West European diet and used toothpaste, which may result in a mean oral intake of 0.06-5.5 mg TiO 2 /kg body weight/ day [3,10,33,34]. Recent human volunteer studies indicate the systemic uptake following ingestion of TiO 2 particles [8,9]. Strikingly, the size range of the TiO 2 particles in the human livers and spleens (i.e. ...
Article
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Background: Titanium dioxide (TiO2) is produced at high volumes and applied in many consumer and food products. Recent toxicokinetic modelling indicated the potential of TiO2 to accumulate in human liver and spleen upon daily oral exposure, which is not routinely investigated in chronic animal studies. A health risk from nanosized TiO2 particle consumption could not be excluded then. Results: Here we show the first quantification of both total titanium (Ti) and TiO2 particles in 15 post-mortem human livers and spleens. These low-level analyses were enabled by the use of fully validated (single particle) inductively coupled plasma high resolution mass spectrometry ((sp)ICP-HRMS) detection methods for total Ti and TiO2 particles. The presence of TiO2 in the particles in tissues was confirmed by Scanning Electron Microscopy with energy dispersive X-ray spectrometry. Conclusions: These results prove that TiO2 particles are present in human liver and spleen, with ≥24% of nanosize (< 100 nm). The levels are below the doses regarded as safe in animals, but half are above the dose that is deemed safe for liver damage in humans when taking into account several commonly applied uncertainty factors. With these new and unique human data, we remain with the conclusion that health risks due to oral exposure to TiO2 cannot be excluded.
... Interestingly, the sites of TiO 2 uptake correspond to regions where first signs of inflammation in CD manifest [49]. In vivo studies on the capacity of TiO 2 to penetrate the gastrointestinal tract revealed that TiO 2 can be found in systemic organs after oral exposition of 10 days505152. In humans, upon one single ingestion of 22 and 45 mg TiO 2 , Ti levels in blood rose after 0.5-2 h, and reached a maximum after 8-12 h [52]. ...
... In vivo studies on the capacity of TiO 2 to penetrate the gastrointestinal tract revealed that TiO 2 can be found in systemic organs after oral exposition of 10 days505152. In humans, upon one single ingestion of 22 and 45 mg TiO 2 , Ti levels in blood rose after 0.5-2 h, and reached a maximum after 8-12 h [52]. Clinical studies also have addressed the influence on TiO 2 on CD patients. ...
Article
Microparticles are small (2), the latter being a white pigment used in toothpaste or sugar toppings. The increasing abundance of microparticles in the Western diet raises the question of the potential risks associated with gastrointestinal diseases such as Crohn’s disease (CD). Accumulation of particles has been shown in cells of Peyer’s patches, but it is not clear whether this also has pathological effects. NLRP3 is a member of the intracellular pattern recognition receptor family and it is part of the inflammasome, a multiprotein complex containing caspase-1 which activates the proinflammatory cytokines interleukin (IL)-1β and IL-18. With regard to recent findings identifying small particles such as asbestos and monosodium urate as NLRP3 activators, TiO2 may be another potential target for inflammasome studies. We found that macrophage-like cells readily take up TiO2 after 6 h. Incubation of cells with TiO2 resulted in the assembly of NLRP3 with caspase-1. This inflammasome assembly correlated with secretion of IL-1β. In intestinal epithelial cells, TiO2 also was found to be ingested. The counting of particles localized intracellularly revealed a dose-dependent increase of TiO2-positive cells. This points to the fact that in humans with a leaky intestinal barrier (such as IBD patients), TiO2 microparticles may be taken up by macrophages and intestinal epithelial cells, may activate the inflammasome and induce IL-1β and IL-18 secretion. This may aggravate inflammation in susceptible individuals.
... Review of oral exposures to TiO 2 and toxic effects in the current literature. An absorption study (Böckmann et al. 2000) determined that humans orally ingesting TiO 2 in capsules containing 23 or 46 mg showed a 5 to 10 times increase of TiO 2 levels in the blood. TiO 2 was absorbed by the GIT in a size-dependent manner, where small particles were absorbed at a better rate than larger ones. ...
... Based on findings from various studies on mammals, it appears that TiO 2 fails to satisfy the 2 conditions on which the JECFA (1969) assessment was based: lack of absorption and lack of accumulation in body tissue. Based on the literature, TiO 2 has clear potential for absorption by mammals after ingestion or injection, as well as for storage in various organs (Huggins and Froehlich 1966;Filho et al. 1991;Jani et al. 1994;Böckmann et al. 2000;Olmedo et al. 2003Olmedo et al. , 2008Wang et al. 2007;Fabian et al. 2008;Sugibayashi et al. 2008;Liu et al. 2009;Duan et al. 2010;Hu et al. 2010;Cui et al. 2011;Xie et al. 2011;Nogueira et al. 2012;Umbreit et al. 2012;Sang, Fei, et al. 2013;Sang, Li, et al. 2013;Shinohara et al. 2014;Tassinari et al. 2014), where it can cause tissue damage and alter biochemical parameters. These properties, however, are most likely dependent on the concentration and size of TiO 2 particles. ...
Article
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From 1916-2011, an estimated total of 165,050,000 metric tonnes of titanium dioxide pigment were produced worldwide. Current safety regulations on the usage of the TiO2 pigment as an inactive ingredient additive in human food are based on legislation from 1969 and are arguably outdated. This paper compiles new research results to provide fresh data for potential risk re-assessment. However, even after 45 years, few scientific research reports have provided truly reliable data. For example, administration of very high doses of TiO2 is not relevant to daily human uptake. Nevertheless, since dose makes the poison, the literature provides a valuable source for understanding potential TiO2 toxicity after oral ingestion. Numerous scientific papers have observed that TiO2 can pass and be absorbed by the mammalian gastrointestinal tract; can bioconcentrate, bioaccumulate, and biomagnify in the tissues of mammals and other vertebrates; has a very limited elimination rate; and can cause histopathological and physiological changes in various organs of animals. Such action is contrary to the 1969 decision to approve the use of TiO2 as an inactive ingredient in human food without an established acceptable daily intake, stating that neither significant absorption nor tissue storage following ingestion of TiO2 was possible. Thus, relevant governmental agencies should reassess the safety of TiO2 as an additive in human food and consider establishing an acceptable maximum daily intake as a precautionary measure. Integr Environ Assess Manag © 2014 SETAC
... Accumulation of inorganic particles (including TiO 2 particles) in intestinal cells may lead to the pathogenesis of inflammatory bowel disease in humans (Lomer et al. 2000(Lomer et al. , 2001(Lomer et al. , 2002(Lomer et al. , 2004(Lomer et al. , 2005Powell et al. 2000Powell et al. , 2010. Based on the literature, TiO 2 has clear potential for absorption by mammals as well as for storage in various organs after ingestion where it can cause tissue damage and alter biochemical parameters (Huggins and Froehlich 1966;Filho et al. 1991;Jani et al. 1994;Böckmann et al. 2000;Olmedo et al. 2003Olmedo et al. , 2008Wang et al. 2007;Fabian et al. 2008;Sugibayashi et al. 2008;Liu et al. 2009;Duan et al. 2010;Hu et al. 2010;Cui et al. 2011;Xie et al. 2011;Nogueira et al. 2012;Umbreit et al. 2012;Sang et al. 2013a,b;Shinohara et al. 2014;Tassinari et al. 2014). TiO 2 has also been indicated as an immunotoxin in vertebrates Jovanovic and Palic 2012;Sang et al. 2012Sang et al. , 2013a. ...
... TiO 2 has also been indicated as an immunotoxin in vertebrates Jovanovic and Palic 2012;Sang et al. 2012Sang et al. , 2013a. Böckmann et al. (2000) observed a 5 to 10 times increase of TiO 2 levels in blood when humans are ingested with capsules containing 23 or 46 mg. Smaller TiO 2 particles were absorbed by the gastrointestinal tract at a better rate than larger ones. ...
... In a study TiO 2 (diameter 160 and 380 nm, 3 and 46 mg) in gelatine capsules was administered for test persons, after which a sizedependent resorption into the blood was detected. The smaller the particles, the quicker the resorption 21 . In another study, female rats were orally administered 12.5 mg rutile TiO 2 /kg (500 nm) for 10 days. ...
... The particles translocated from the Pyer's patches into the mesenteric lymph and then to systemic organs (i.e., liver, spleen, blood, bone marrow, and kidney). Bockmann et al. [26] also found the uptake of the TiO 2 nanoparticles from the gastrointestinal tract into the blood. ...
Article
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Nanotechnology is the understanding and control of matter at the nanoscale, at dimensions between approximately 1–100 nm, where unique phenomena such as improved physical, chemical, biological properties enable novel applications. The increasing use of engineered nanomaterials (ENMs) in consumer and industrial products has also aroused global concern regarding their fate in biological systems and resulting in a demand for parallel risk assessment. A variety of ENMs with different chemical compositions, synthesized through different methods, differing in size, shape, surface coatings, etc. have been shown to be genotoxic and cytotoxic in different organ specific cell lines (in vitro) and mouse. However there is a dilemma in the selection and validation of the test methods for the ENMs characterization, dose selection, cytotoxicity and genotoxicity assessment, because of the altered behaviour of ENMs as compared to the chemicals. A multidisciplinary team effort from material scientists, molecular biologists, toxicologists and physicists is necessary as it will facilitate the interlinking of different facets of nanotoxicology thus aiding in the understanding of cellular responses to nanomaterials exposure and mechanisms involved.
... However, uptake of polystyrene microparticles into the Peyer's patches may be lower in humans (Pappo and Ermak, 1989;Lavelle et al., 1995) since there are <5% M cells in the Peyer's patches in humans compared to 20% in rabbits and in 10% in rodents (Brayden et al., 2005). Persorption may occur when aging enterocytes are sloughed off at the tip of the villi and particles of various sizes may enter the body through the denuded surface (Bockmann et al., 2000;Powell et al., 2010). This process has been observed for colloidal gold nanoparticles (Hillyer and Albrecht, 2001), metallic iron (Volkheim et al., 1969) and starch particles (Hillyer and Albrecht, 2001). ...
Chapter
The main strategies to alleviate mineral deficiencies are food diversification, food fortification or supplementation. Absorption of poorly soluble iron compounds can be improved by particle size reduction. Reducing the size of mineral and trace element compounds to the nanoscale is a promising recent development to maximize absorption. This chapter analyzes the usefulness of this approach for different minerals. The high specific surface area and the small size of nano-structured compounds are one of their most important characteristics in their use for nutritional applications. The chapter provides a review of the literature and potential applications for selected trace elements and minerals such as iron and zinc. Since nano-sizing compounds increase their surface area, this may increase dissolution, improve absorption, and result in less inert particulate matter in the gut. However, it is still possible that ingested nano-structured compounds may end up in the intestine without further dissolution or disintegration.
... For example, in rats dosed orally with radiolabelled functionalized C60 fullerenes, 98 % were cleared in the faeces within 48 hours, while the rest was eliminated via urine, indicating uptake of the particles into the blood [67]. Also, uptake of larger TiO 2 particles (150 -500 nm) into the blood and distribution to the liver was observed [68]. ...
Article
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Nanotechnology and engineered nanostructures (ENSs) are becoming part of everyday life, starting from industrial application, even in food products, to gene therapy. Thus, tons and tons of nanoparticles (NPs) enter the environment and indirectly or directly -into the biological systems, including the human body. There are many con-troversial papers that describe interactions of the ENSs with biological systems and raise concern that intentional or unintentional human exposure to certain types of ENSs, may lead to significant health, i.e. toxicological effects. Because of our insufficient and contradictory knowledge about the health effects associated with the ENSs exposure, the aim of this paper is to summarize and systemize the already confirmed data and the latest found facts about ENSs and their health effects and to discuss the future opportunities and tasks in the field of nanotoxicology.
... With increasing industrial production of engineered nano and microparticles, questions have been raised on their effects on humans and animals[1][2][3][4]. Engineered particles enter the body by inhalation[5], ingestion[6]and by corrosion of implants[7,8], while possibilities of injection of engineered nanoparticles for imaging and therapeutic purposes are being explored[9,10]. In order to protect ourselves from their (potentially) harmful effects and use them beneficially, their interactions with living beings should be well studied and the underlying biochemical and biophysical mechanisms which take place on the mesoscopic and nanoscopic level[11][12][13][14][15][16][17]should be better understood. ...
Article
Background Massive industrial production of engineered nanoparticles poses questions about health risks to living beings. In order to understand the underlying mechanisms, we studied the effects of TiO2 and ZnO agglomerated engineered nanoparticles (EPs) on erythrocytes, platelet-rich plasma and on suspensions of giant unilamelar phospholipid vesicles. Results Washed erythrocytes, platelet-rich plasma and suspensions of giant unilamelar phospholipid vesicles were incubated with samples of EPs. These samples were observed by different microscopic techniques. We found that TiO2 and ZnO EPs adhered to the membrane of washed human and canine erythrocytes. TiO2 and ZnO EPs induced coalescence of human erythrocytes. Addition of TiO2 and ZnO EPs to platelet-rich plasma caused activation of human platelets after 24 hours and 3 hours, respectively, while in canine erythrocytes, activation of platelets due to ZnO EPs occurred already after 1 hour. To assess the effect of EPs on a representative sample of giant unilamelar phospholipid vesicles, analysis of the recorded populations was improved by applying the principles of statistical physics. TiO2 EPs did not induce any notable effect on giant unilamelar phospholipid vesicles within 50 minutes of incubation, while ZnO EPs induced a decrease in the number of giant unilamelar phospholipid vesicles that was statistically significant (p < 0,001) already after 20 minutes of incubation. Conclusions These results indicate that TiO2 and ZnO EPs cause erythrocyte aggregation and could be potentially prothrombogenic, while ZnO could also cause membrane rupture.
... 82 This study supported earlier findings where blood samples contained increased levels of TiO 2 after ingestion of 160-and 380-nm TiO 2 NPs. 83 The presence of reflective particles in blood was interpreted as evidence of the presence of TiO 2 particles, but this was not confirmed by direct analysis of particle composition, for example, by single particle Inductively coupled plasma mass spectrometry (ICPMS). ...
Article
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Ingestion of engineered nanomaterials is inevitable due to their addition to food and prevalence in food packaging and domestic products such as toothpaste and sun cream. In the absence of robust dosimetry and particokinetic data, it is currently challenging to accurately assess the potential toxicity of food‐borne nanomaterials. Herein, we review current understanding of gastrointestinal uptake mechanisms, consider some data on the potential for toxicity of the most commonly encountered classes of food‐borne nanomaterials (including TiO2, SiO2,ZnO, and Ag nanoparticles), and discuss the potential impact of the luminal environment on nanoparticle properties and toxicity. Much of our current understanding of gastrointestinal nanotoxicology is derived from increasingly sophisticated epithelial models that augment in vivo studies. In addition to considering the direct effects of food‐borne nanomaterials on gastrointestinal tissues, including the potential role of chronic nanoparticle exposure in development of inflammatory diseases, we also discuss the potential for food‐borne nanomaterials to disturb the normal balance of microbiota within the gastrointestinal tract. The latter possibility warrants close attention given the increasing awareness of the critical role of microbiota in human health and the known impact of some food‐borne nanomaterials on bacterial viability. WIREs Nanomed Nanobiotechnol 2018, 10:e1481. doi: 10.1002/wnan.1481 This article is categorized under: 1Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
... , where 'old' enterocytes are extruded from the villus into the gut lumen, leaving 'holes' in the epithelium, which allow translocation of even large particles, such as starch and pollen515253. ...
... retained one week, mostly in the liver (80%, depending on time course). Other studies using ultrafine 192 Ir did not show significant up-take in the GI tract [41,49], whereas earlier studies with larger TiO 2 particles (150– 500 nm) found up-take into the blood and movement to the liver [50,51]. Apparently, there are differences in GI tract up-take also depending on both particle surface chemistry and particle size. ...
Article
Biocompatibility, biodistribution, biodegradation, inflammation and interference with cells and normal functioning of organs, among other factors, will determine the toxicity of engineered inorganic nanoparticles and carbon nanostructures, and therefore the extent of their use. Recent examples in the literature show that engineered inorganic nanoparticles and carbon nanostructures, which may incidentally or intentionally enter into contact with living organisms, normally, at realistic doses, do not cause acute toxic effects. However, their prolonged interaction with living organisms may disrupt normal activity leading to malfunctioning and diseases. Indeed, observed nanoparticle-biological interactions, which can be used to detect and to manipulate biological states and therefore heal damaged organs, could also lead to environmental and human health hazards. In this scenario, how those nanostructures enter and are distributed inside the body is critical.
... However, many studies showed that nano TiO 2 can be absorbed by gastrointestinal tract, it can bio-accumulate and cause changes in various organs of animals (Jani et al. 1994, Bockmann et al. 2000, Cui et al. 2010, Koeneman et al. 2010, Wang et al. 2013, Sang et al. 2014, Tassinari et al. 2014, Shi et al. 2013, Jovanovic 2015. Some other studies (Cho et al. 2013, Jones et al. 2015, MacNicoll et al. 2015 show limited absorption in the gastrointestinal tract. ...
Article
Novel nanoparticles containing non-stick coatings have been developed for food contact applications such as frying pans. Possible release of nanoparticles from such coatings into food is not known. In this paper, the characterisation of commercially available non-stick coatings was performed by use of FTIR, electron and optical microscopy, EDXS and XRD analysis. Characterisation revealed that the coatings contained micron- and nanosized rutile TiO2 particles, and quartz SiO2 embedded in a silicone polymer matrix. In order to estimate possible migration of TiO2 nanoparticles from coatings into food, migration tests into simulants (deionised water, 3 % acetic acid and 5 g/l citric acid) were performed (2 hours at 100 °C), and thermal and mechanical degradation of the matrix was studied. Simulants were analysed by ICP-MS after ultrafiltration and by microwave assisted digestion. The concentration of titanium-containing particles that migrated into simulants was up to 861 µg/l (147 µg/dm²).Titanium was present in simulants in ionic form as well. The presence of TiO2 nanoparticles in 3 % acetic acid was confirmed by SEM-EDXS analysis. Thermal stability study (TG/DSC MS analysis) did not show degradation of the matrix under foreseeable conditions of use, but mechanical degradation studies (scratch and tribological testing) showed possible release (microgram quantities per punched sample) of titanium-containing nanoparticles. The matrix degradation results were confirmed by observations of the morphology of the same type of coatings actually used for food preparation. Dissolution from the surface and matrix degradation can both contribute to nanoparticles release from this type of non-stick food contact coatings.
... TiO 2 particles have been shown to accumulate in M cells of Peyer's patches and are passed on to underlying macrophages [17]. In vivo studies on the capacity of TiO 2 NPs to penetrate the gastrointestinal tract revealed that TiO 2 could be found in systemic organs after an oral exposure of 10 days [18] [19]. TiO 2 NPs have also been shown to be absorbed from the gastrointestinal tract (25, 80, and 155 nm; 5 g/kg BW; single oral dose; mice) [20]. ...
Article
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Listeria monocytogenes is the agent of listeriosis, a food-borne disease. It represents a serious problem for the food industry because of its environmental persistence mainly due to its ability to form biofilm on a variety of surfaces. Microrganisms attached on the surfaces are a potential source of contamination for environment and animals and humans. Titanium dioxide nanoparticles (TiO2 NPs) are used in food industry in a variety of products and it was reported that daily exposure to these nanomaterials is very high. Anti-listerial activity of TiO2 NPs was investigated only with UV-irradiated nanomaterials, based on generation of reactive oxigen species (ROS) with antibacterial effect after UV exposure. Since both Listeria monocytogenes and TiO2 NPs are veicolated with foods, this study explores the interaction between Listeria monocytogenes and non UV-irradiated TiO2 NPs, with special focus on biofilm formation and intestinal cell interaction. Scanning electron microscopy and quantitative measurements of biofilm mass indicate that NPs influence both production and structural architecture of listerial biofilm. Moreover, TiO2 NPs show to interfere with bacterial interaction to intestinal cells. Increased biofilm production due to TiO2 NPs exposure may favour bacterial survival in environment and its transmission to animal and human hosts.
... This is likely to be genuine background TiO 2 as implied by prior ICP-MS analyses of baseline human blood samples (7). Food, toothpaste, nutraceuticals, and pharmaceutical products account for the average UK adult ingesting around 3 mg TiO 2 per day (6), some of which reaches the blood stream (7,8). Hence, due to widespread daily human exposure to TiO 2 it is likely that baseline blood samples will always have a degree of 'natural background' signal, so it is difficult to ascertain with certainty where the limit of detection exists for imaging flow cytometry. ...
Article
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Pigment grade titanium dioxide is composed of sub-micron sized particles, including a nanofraction, and is widely utilized in food, cosmetic, pharmaceutical, and biomedical industries. Oral exposure to pigment grade titanium dioxide results in at least some material entering the circulation in humans, although subsequent interactions with blood immune cells are unknown. Pigment grade titanium dioxide is employed for its strong light scattering properties, and this work exploited that attribute to determine whether single cell–particle associations could be determined in immune cells of human whole blood at “real life” concentrations. In vitro assays, initially using isolated peripheral blood mononuclear cells, identified titanium dioxide associated with the surface of, and within, immune cells by darkfield reflectance in imaging flow cytometry. This was confirmed at the population level by side scatter measurements using conventional flow cytometry. Next, it was demonstrated that imaging flow cytometry could quantify titanium dioxide particle-bearing cells, within the immune cell populations of fresh whole blood, down to titanium dioxide levels of 10 parts per billion, which is in the range anticipated for human blood following titanium dioxide ingestion. Moreover, surface association and internal localization of titanium dioxide particles could be discriminated in the assays. Overall, results showed that in addition to the anticipated activity of blood monocytes internalizing titanium dioxide particles, neutrophil internalization and cell membrane adhesion also occurred, the latter for both phagocytic and nonphagocytic cell types. What happens in vivo and whether this contributes to activation of one or more of these different cells types in blood merits further attention. © 2017 International Society for Advancement of Cytometry
... It should be noted that nanoparticles can enter the body and living tissues via different routes as mentioned by Bockmann et al. including water, food, drugs and cosmetics [1]. Therefore, this type of very tiny particles can enter to the body intentionally or unintentionally as it enters into many formulations and industries that we all use in our daily lives. ...
Article
Objective: The goal of this study is to assess and confirm the clinical importance of measurement of positive and negative acute phase proteins parameters as biomarkers for inflammation; and alterations in blood picture induced by nanoparticles instead of back to tissue biopsy and histopathology. Methods: Rats were randomly grouped into three groups, 1st group acted as control group and received 1 ml/d distilled water; the 2nd group received 1 ml of distilled water containing iron oxide at 100 μg/kg concentrations using stomach tube; while the 3rd group received 1 ml of distilled water containing iron oxide at 150 μg/kg concentrations, for a period of 4 weeks. The clinic-pathological effects were observed by estimating the alterations in different functional parameters of the liver in serum using chemical kits and in the hematological parameters by using autohematology analyzer. Results: Alterations were in the form of significant elevations of AST, ALT and ALP enzyme activities; significant decreases in total and conjugated bilirubin; significant increases in all positive acute phase proteins and decreases in all negative acute phase ones; with significant increases in IL-1α, IL-6 and TNF-α cytokines and a disturbance in lipogram appearing as remarkable high total lipids, cholesterol, LDL-C, VLDL-C, with significant decrease in HDL-C. These results were associated with alterations in hematological parameters and occurrence of anemia in both 2nd and 3rd groups. Conclusion: Nanoparticles have double-edged sword that ultra-structure of these articles seem to have advantage in the treatment, but in the same time may cause marked injuries to the vital organs as liver and related functions.
... These ingested nanoparticles are translocated to different organs by getting absorbed into the blood through the intestinal lumen (Pietroiusti et al. 2013). The translocation of TiO 2 nanoparticles have been reported to various organs in body through the gastrointestinal (GI) track via blood (Böckmann et al. 2000). Nanoparticles size and shape imparts in their toxicity, it has been reported that triangular shaped nanoparticles are more toxic than spherical nanoparticle (Huang et al. 2007;Chan et al. 2008;Dasgupta et al. 2016b). ...
Article
Food nanotechnology has been rapidly growing in last decade due to the unique properties of nanomaterials. Nonetheless, the presence of nanomaterials in food induces potential risks of toxicity because nanoparticles can easily cross the barriers of human anatomy, through respiratory, dermal, and gastrointestinal routes. In that respect, some countries such as India do not have strict regulations to control nanofood products. This review describes nanomaterial–cell interactions that induce toxicological responses. We discuss the toxicity of food nanomaterials; mechanisms of oxidative stress, genotoxicity and carcinogenicity; and safety regulations.
... However, recent human volunteer studies show elevated blood Ti levels 6 hrs. after ingestion of food grade TiO 2 [7,8]. Recent studies with TiO 2 nanoparticles show that repeated exposure to these particles may result in significant tissue accumulation at a higher age [9][10][11]. ...
... Volkheimer's concept of movement across 'gaps' present at the tip of villous subsequently loss of enterocyte(s) to the gut lumen. This route is probably approached by small and large nanoparticles, but, quantitatively, it is less likely to be competent ( [46][47][48]). (d) Putative paracellular uptake [49]. ...
Chapter
Full-text available
Specialized microfold cells (M cells) within the follicle-associated endothelium of intestinal Peyer’s patches play a key role in body’s defence mechanism by endocytosing macromolecules. Particulate uptake by the Peyer’s patch offers a very attractive avenue for delivering drugs through the peroral route. This review describes the pathway of drug delivery by Peyer’s patch targeting and its associated advantages. Disorders affecting the function of the lymphatic and immune system can be treated by targeting the active moieties at the Peyer’s patch. Drugs have been delivered to the Peyer’s patch for autoimmune disorders like HIV/AIDS, rheumatoid arthritis, chronic inflammatory disorders, tuberculosis, psoriasis and cancer. Several drug delivery systems like nanoparticles, dendrimers, microspheres, SMEDDS and liposomes have been reviewed for oral lymphatic delivery of small-sized drugs as well as macromolecular drugs like vaccines for immunogenic response. Factors such as surface charge, size, hydrophobicity, surface modification and conjugation have been found to be important determinants in modulating the targeting of these drugs to Peyer’s patches. These novel drug carriers are particularly useful in improving the oral bioavailability and efficacy of the drugs by selective utilization of lymphatic absorption avoiding the portal circulation. Further research in the direction of elucidating the mechanisms of drug transport to the intestinal lymphatic system specifically the cellular and intracellular events may help in delivering a greater number of drugs through the Peyer’s patch.
... Al-Jubory and Handy (2012) recently reported nystatin-sensitive transepithelial uptake of Ti from TiO 2 NPs across the isolated perfused intestine of trout, and found resting Ti uptake rates of around 1-3.4 nmol g −1 h −1 ; similar to that of other nonessential divalent metals (e.g., Handy, 2003). In humans, particle size and dose-dependent increase of blood total Ti concentration following oral ingestion of anatase TiO 2 have been observed (Bockmann et al., 2000), providing some evidence for a particle size-effect on dietary uptake. Studies using cultured Caco-2 cells (a human-derived intestinal cell line) also suggest some Ti uptake, possibly of intact particles, without disruption of the epithelium (Koeneman et al., 2010). ...
Article
Full-text available
The gastrointestinal uptake of different crystal structures of TiO2 was investigated using Caco-2 intestinal cells. Caco-2 monolayers exhibited time-dependent, saturable uptake of Ti from TiO2 exposures of 1mg l(-1) over 24h, which was influenced by crystal type. Initial uptake rates were 5.3, 3.73, 3.58 and 4.48 nmol mg(-1) protein h(-1) for bulk, P25, anatase and rutile forms respectively. All exposures caused elevations of Ti in the cells relative to the control (ANOVA P<0.05). Electron micrographs of the Caco-2 monolayer showed the presence of particles inside the cells, and energy dispersive spectroscopy (EDS) confirmed the composition as TiO2. Incubating the cells with 120 IU nystatin (putative endocytosis inhibitor) or 100μmol l(-1) vanadate (ATPase inhibitor) caused large increases in Ti accumulation for all crystal types relative to controls (ANOVA P<0.05), except for the rutile form with vanadate. Incubating the cells with 90μmol l(-1) genistein (tyrosine kinase inhibitor) or 27μmol l(-1) chloropromazine (clathrin-mediated endocytosis inhibitor) caused a large decrease in Ti accumulation relative to the controls (ANOVA P<0.05). Cell viability measures were generally good (low LDH leak, normal cell morphology), but there were some changes in the electrolyte composition (K(+), Na(+), Ca(2+), Mg(2+)) of exposed cells relative to controls. A rise in total Ca(2+) concentration in the cells was observed for all TiO2 crystal type exposures. Overall, the data shows that Ti accumulation for TiO2 NP exposure in Caco-2 cells is crystal structure-dependent, and that the mechanism(s) involves endocytosis of intact particles.
Article
Humans have evolved with oral exposure to dietary microparticles and nanoparticles as a normal occurrence but the ever-growing exploitation of nanotechnology is likely to increase exposure further, both qualitatively and quantitatively. Moreover, unlike the situation with respirable particles, relatively little is known about gastrointestinal intake and handling of nanoparticles. With a long term interest in gut exposure and responses to dietary microparticles, our group is now applying its expertise to nanoparticles in the gastrointestinal tract. Here we aim to address (i) the current challenges associated with the characterisation of particle-host or particle-cell interactions, (ii) the origin and mechanisms of uptake of particles in the gastrointestinal tract, especially via the Peyer's patch and (iii) potential cellular effects of nanoparticles in the generation of reactive oxygen species and inflammasome activation, or microparticles in their adjuvant activity in pro-inflammatory signalling and immune responsiveness.
Article
Replaceable brush units of powered toothbrushes (PTBs) can contain metal parts made of nickel and chromium bearing alloy. These alloy ingredients have allergenic potential, and may contaminate toothpaste and the mouth during use. Here I quantify metals abraded from PTBs. A leading brand of PTB was used in a simulated intraoral environment with three leading brand toothpastes, and post-brushing samples were analysed for iron, chromium, nickel, molybdenum, and manganese by certified laboratories using standard methods. Results showed tartar control toothpaste abraded most metal, and caused discolouration of toothpaste slurry. Discolouration of toothpaste slurry, as a useful indicator of metal abrasion, was limited to one toothpaste brand, and not useful across brands.
Chapter
An exponential increase in products containing titanium dioxide nanomaterials (TiO 2 ), in agriculture, food and feed industry, lead to increased oral exposure to these nanomaterials (NMs). Thus, the gastrointestinal tract (GIT) emerges as a possible route of exposure that may drive systemic exposure, if the intestinal barrier is surpassed. NMs have been suggested to produce adverse outcomes, such as genotoxic effects, that are associated with increased risk of cancer, leading to a concern for public health. However, to date, the differences in the physicochemical characteristics of the NMs studied and other variables in the test systems have generated contradictory results in the literature. Processes like human digestion may change the NMs characteristics, inducing unexpected toxic effects in the intestine. Using TiO 2 as case-study, this chapter provides a review of the works addressing the interactions of NMs with biological systems in the context of intestinal tract and digestion processes, at cellular and molecular level. The knowledge gaps identified suggest that the incorporation of a simulated digestion process for in vitro studies has the potential to improve the model for elucidating key events elicited by these NMs, advancing the nanosafety studies towards the development of an adverse outcome pathway for intestinal effects.
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A southern Italian area that is characterized by large outcrops of rocks that are rich in titanium oxide (TiO2) phases were investigated to determine the mineralogical risk induced by the natural dispersion of TiO2 minerals. Rock, sediment and surface water samples were collected to determine the physicochemical and mineralogical factors (i.e., size distribution, morphology and alteration) indicative of potential TiO2 toxicity. X-ray diffraction data suggested that titanium oxides were present as rutile and anatase. Scanning electron microscopy images showed elongated TiO2 morphologies; fibres were found as either isolated or embedded/enclosed in flake-like phyllosilicates. The concentration of fibres in stream water ranged from 1.7 to 4.6 million fibres per litre. The highest fibre amounts in the sediments were in the <8-µm fraction, while single fibres were primarily concentrated in the <2-µm fraction. The results indicate that titanium oxide minerals represent a natural source of environmental risk and that the geomineralogical characterization of rich TiO2 areas is indispensable for understanding their geoavailability, dispersion and distribution.
Article
Nanotechnology has seen exponential growth in last decade due to its unique physicochemical properties; however, the risk associated with this emerging technology has withdrawn ample attention in the past decade. Nanotoxicity is majorly contributed to the small size and large surface area of nanomaterials, which allow easy dispersion and invasion of anatomical barriers in human body. Unique physio-chemical properties of NPs make the investigation of their toxic consequences intricate and challenging. This makes it important to have an in-depth knowledge of different mechanisms involved in nanomaterials's action as well as toxicity. Nano-toxicity has various effects on human health and diseases as they can easily enter into the humans via different routes, mainly respiratory, dermal and gastrointestinalroutes. This also limits the use of nanomaterials as therapeutic and diagnostic tools. This review focuses on the nanomaterial-cell interactions leading to toxicological responses. Different mechanisms involved in nanoparticle-mediated toxicity with the main focus on oxidative stress, genotoxic and carcinogenic potential has also been discussed. Different methods and techniques used for the characterization of nanomaterials in food and other biological matrices have also been discussed in detail. Nano-toxicity on different organs - with the major focus on the cardiac and respiratory system - have been discussed. Conclusively, the risk management of nanotoxicity is also summarized. This review provides a better understanding of the current scenario of the nanotoxicology, disease progression due to nanomaterials, and their use in the food industry and medical therapeutics. Briefly, the required rules, regulations and the need of policy makers has been discussed critically.
Thesis
La maladie de Crohn (MC) est une maladie inflammatoire chronique de l’intestin dont l’étiologie complexe comprend des facteurs génétiques, infectieux, environnementaux ainsi qu’une composante épigénétique. Il a été montré des profils de méthylation de l’ADN modifiés chez les patients MC ainsi que des carences en molécules donneuses de groupements méthyles (folate et vitamine B12). L’objectif de ce projet était d’étudier l’impact d’un régime alimentaire enrichi en molécules donneuses de groupements méthyles (HMD), participant au métabolisme de la méthylation de l’ADN, sur la physiologie intestinale et l’expression des gènes. Nous avons montré qu’un régime HMD favorise le développement de certaines populations bactériennes ayant des effets bénéfiques sur la physiologie intestinale. De plus, ce régime modifie les niveaux de méthylation de l’ADN et l’expression de nombreux gènes. En particulier, l’augmentation du niveau de méthylation du promoteur du gène CEACAM6 (impliqué dans l’adhésion des Escherichia coli adhérents et invasifs (AIEC) chez les patients MC) ainsi qu’une diminution de son expression ont été observées. En conclusion, une supplémentation en molécules donneuses de méthyles pourrait permettre de réguler la composition du microbiote intestinal et l’expression de gènes participant au déclenchement et au maintien de l’inflammation intestinale dans la MC.
Article
Objective: The objective of this research was to determine the size, shape and aggregation of titanium dioxide (TiO2 ) particles which are used in sun lotion as UV-blocker. Methods: Overall, six sunscreens from various suppliers and two reference substances were analysed by electron microscopy (EM) techniques in combination with energy dispersive X-ray spectroscopy (EDS). Because of a high fat content in sun lotion it was impossible to visualize the TiO2 -particles without previous EM sample preparation. Different defatting methods for TiO2 from sun screens were tested. A novel sample preparation method was developed which allowed the characterisation of TiO2 particles with the help of EM and EDS. Results: Aggregates of titanium dioxide with the size of primary particles varying between 15 and 40 nm were observed only in five products. In the sun lotion with the highest SPF only few small aggregates were found. In the sun screen with the lowest SPF the largest aggregates of TiO2 particles were detected with sizes up to 1.6 μm. In one of the sun lotions neither TiO2 nor ZnO were found in spite of the labelling. Instead approx. 500 nm large diamond-shaped particles were observed. These particles are composed of an organic material as only carbon was detected by EDS. Conclusion: A novel defatting method for sample preparation of titanium dioxide nanoparticles used in sun cosmetics was developed. This method was applied to six different sun lotions with SPF between 30 and 50+. TiO2 particles were found in only five sunscreens. The sizes of the primary particles were below 100 nm and according to the EU Cosmetic Regulation have to be listed on the package with the term "nano". This article is protected by copyright. All rights reserved.
Chapter
Food nanotechnology has seen exponential growth in last decade due to its unique physicochemical properties; however, the risk associated with this emerging technology has withdrawn ample attention in the past decade. Developing novel food-product for better efficiency is important but analyzing the short term as well as long term toxic effects is more important and that is why rules, regulations and other controlling measures. Nanotoxicity is majorly contributed to the small size and large surface area of nanomaterials, which allow easy dispersion and invasion of anatomical barriers in human body. Unique physio-chemical properties of nanomaterials make the investigation of their toxic consequences intricate and challenging. Nano-toxicity has various effects on human health and diseases as they can easily enter into the humans via different routes, mainly respiratory, dermal and gastrointestinalroutes.
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E171 (titanium dioxide) is a food additive that has been authorized for use as a food colorant in the European Union. The application of E171 in food has become an issue of debate, since there are indications that it may alter the intestinal barrier. This work applied standardized and validated methodologies to characterize representative samples of 15 pristine E171 materials based on transmission electron microscopy (TEM) and single-particle inductively coupled plasma mass spectrometry (spICP-MS). The evaluation of selected sample preparation protocols allowed identifying and optimizing the critical factors that determine the measurement of the particle size distribution by TEM. By combining optimized sample preparation with method validation, a significant variation in the particle size and shape distributions, the crystallographic structure (rutile versus anatase), and the physicochemical form (pearlescent pigments versus anatase and rutile E171) was demonstrated among the representative samples. These results are important for risk assessment of the E171 food additive and can contribute to the implementation of the European Food Safety Authority (EFSA) guidance on risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain.
Article
Titanium dioxide is one of the most commonly used pharmaceutical excipients. It is widely used as a white pigment in tablet and pellet coatings. However, it has recently been under massive criticism as a number of studies suggest a cancerogenic potential. It can therefore no longer be taken for granted that TiO2 will continue to be universally available for drug products. Finding suitable alternatives is hence of special relevance. In this study a number of different pigments were coated on tablets and their covering potential analyzed. None of the alternative pigments showed comparable effectiveness and efficiency to TiO2, though the CaCO3/CaHPO4-based coating showed the second-best results. Regarding the ability to protect photosensitive active ingredients, ZnO showed a comparable potential as TiO2, while all other pigments failed. Using the alternative pigments as markers for in-line Raman spectroscopy as a Process Analytical Technology was challenging and led to increased prediction errors. Again, the CaCO3/CaHPO4-based coating was the only of the tested alternatives with satisfying results, while all other pigments led to unacceptably high prediction errors.
Article
Amifostine (Ethyol, WR-2721) is a cytoprotective drug approved by the US Food & Drug Administration for intravenous administration in cancer patients receiving radiation therapy and certain forms of chemotherapy. The primary objective of this project was to develop orally active amifostine nanoparticles using spray drying technique. Two different nanoparticle formulations (Amifostine-PLGA (0.4:1.0 and 1.0:1.0)) were prepared using a Buchi B191 Mini Spray Dryer. A water-in-oil emulsion of amifostine and PLGA (RG 502) was spray dried using an airflow of 600 L h(-1) and input temperature of 55 degrees C. A tissue distribution study in mice was conducted following oral administration of the formulation containing drug-polymer (0.4:1.0). The efficiency of encapsulation was 90% and 100%, respectively, for the two formulations while the median particle sizes were 257 and 240 nm, with 90% confidence between 182 and 417 nm. Since amifostine is metabolized to its active form, WR-1065, by intracellular alkaline phosphatase, the tissue levels of WR-1065 were measured, instead of WR-2721. WR-1065 was detected in significant amounts in all tissues, including bone marrow, jejunum and the kidneys, and there was some degree of selectivity in its distribution in various tissues. This work demonstrates the feasibility of developing an orally effective formulation of amifostine that can be used clinically.
Article
Titanium dioxide (rutile) particles of nominal size 500 nm were administered as a 0.1 ml dose of a 2.5% w/v suspension (12.5 mg kg−1) to female Sprague Dawley rats, by oral gavage daily for 10 days. Organs and tissues such as Peyer's patches, small intestine, colon, mesentery network and nodes, peritoneal tissue, liver, spleen, heart and kidney were removed for histology, scanning electron microscopy, and spectroscopic analysis for titanium using the technique of inductively coupled plasma atomic emission spectroscopy. Histological and chemical analysis proved the presence of titanium dioxide particles in all the major tissues of the gut associated lymphoid tissue (GALT), and demonstrated that 500 nm tianium dioxide particles were translocated to systemic organs such as the liver and the spleen. Titanium dioxide particles were also found in the lung and perioneal tissues, but were not detected in the heart or the kidney. The uptake of inert particulate matter, such as titanium dioxide, used in pharmaceuticals and food poses the question whether insolubility and inertness necessarily guarantess their innocuous nature.
Article
Titanium dioxide (TiO2) dusts exhibit a hemolytic behavior against human erythrocytes in vitro. The hemolytic activity depends on the crystal lattice of TiO2—rutile being practically inert and anatase having significant activity. In a preliminary in vivo experiment both types of TiO2 failed to increase the proline hydroxylase level in rat lung when measured four weeks after TiO2 inhalation, although proline hydroxylase levels have been shown to increase in the initial stages of fibrosis. This negative finding does not, however, eliminate the possibility of fibrogenicity because the incubation period was short. The retention of anatase dust in the lungs was also remarkably greater than that of rutile. Because of the found properties of anatase, more extensive studies should be performed to determine the possible biological effects of inhaled TiO2, especially those of anatase.
This chapter discusses the physiology and pharmacology of persorption of particles. The observations described in this chapter effectively disposed of any doubt that, such large particles were capable of passing through the intestinal mucosa. The question whether persorption is a physiological or pathologicalprocess remains a purely academic one. Absorption of a particle of this size by the enterocyte body can be ruled out. Paracellular passage between the enterocytes has been demonstrated as the mechanism of persorption. Actually, the closely interlocked enterocyte layer (the so-called tight junction) forms a fairly impenetrable barrier to passage of particles in this way. The only interruption in this network of tight junctions is because of goblet cells. The electron scanning microscope reveals, a loosening of the tight junctions of the intestinal mucosa occurs in the immediate neighborhood of the goblet cells. Spontaneous loosening is also possible as a result of cell desquamation.
Article
Intraperitoneal (i.p.) and intravenous (i.v.) injection of 44Ti in a chloride solution into mice produced no detectable translocation in body fluids. There was no obvious interorgan exchange up to 16 days after injection. The whole body biological retention half-lives had a mean of 642 days for both routes, another indication of 44Ti's insolubility in body fluids. Absorption from the gastrointestinal (g.i.) tract after administration by stomach tube was negligible. The threshold limit value (TLV) for titanium in air, based upon nuisance dust, is acceptable based upon the results of this study.