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Blood levels of titanium before and after oral administration of titanium dioxide
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.
... 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]. ...
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. ...
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). ...
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.
... Pele et al. treated the volunteers whom they found to have normal intestinal permeability with TiO 2 capsule by mouth (50 mg in 2 doses) found that the amount of particles in the blood of the volunteers reached the highest level in the 6th hour [19]. In another volunteer study, TiO 2 particles administered orally were detected in the blood and it was emphasized that the amount determined showed personal differences [20]. Considering that TiO 2 is frequently used in food additives and drug content, and Ti is used in medical implants, this element has an important place in our lives. ...
Titanium dioxide (TiO2) nanoparticles are widely used in food, cosmetics, biomedical implants, and pharmaceutical fields. Their effect on blood coagulation in human plasma and blood have been demonstrated. In this study, it is aimed to investigate whether the TiO2 particles of different shapes and sizes directly activate an intrinsic coagulation pathway protein factor XII (FXII). Two different TiO2 particles were morphologically characterized and prepared in physiological buffer solutions. The hydrodynamic radii and zeta potentials were measured using dynamic light scattering (DLS). The particles were incubated at 20, 10, 5 and 2.5 µg/ml (final concentrations) with 5 µg/ml FXII protein and enzymatic activity was measured with the help of a substrate of activated FXII (FXIIa). The enzyme activity was also measured in plasma in the presence and absence of corn trypsin inhibitor (CTI), a highly specific inhibitor of FXIIa. It has been found that FXII protein is activated in a dose-dependent manner by TiO2 particles, and this activation has been determined to occur independently of the particle hydrodynamic radius. However, it has been found that the zeta potential values of the particles in the buffer solution are directly related to the FXII enzymatic activity. It has been shown that TiO2 particles can activate the coagulation protein FXII based on surface charge distributions. Considering the possible effects of these materials on blood coagulation, zeta potential values should be considered when used in food and pharmaceutical production. [Med-Science 2021; 10(3.000): 912-7]
Titanium is a naturally occurring element. The commercially most important titanium compound is pigmentary TiO 2 , whereas nano‐scaled TiO 2 represents only a small amount on the market. Since humans are exposed to TiO 2 at workplace or through consumer products, a thorough evaluation of its potential toxicity has been summarized herein. Dermal absorption of TiO 2 is deemed to be negligible, whereas oral and inhalation absorption has been reported but is assumed to be very low. TiO 2 has been shown to be of low acute oral, dermal, and inhalation toxicity and is considered to be void of skin and eye‐irritating properties. It also does not show any potential for skin and respiratory sensitization. Oral long‐term toxicity studies in rats report no adverse effects, and due to lack of dermal absorption of TiO 2 , it is assumed that dermal exposure is also not a hazard. TiO 2 does not show any primary mutagenicity and is also void of reproductive or developmental toxicity. However, in long‐term inhalation toxicity studies in rats, inflammation, fibroproliferative effects, and lung tumor formation has been observed but only under conditions of excessive particle lung overload. Carcinogenicity under such extreme conditions with complete cessation of lung clearance is considered to not imply a cancer hazard for humans, which is in line with epidemiological studies showing no causative link between TiO 2 particle exposure and cancer risk in humans. However, based on the available animal database, IARC in the past classified TiO 2 as possibly carcinogenic to humans, and the Risk Assessment Committee of ECHA also concluded that TiO 2 warrants a Category 2 classification for carcinogenicity.
A substantial part of the plastic produced worldwide ends up in the environment and degrades into nano- and microplastics. The particles are ubiquitously present in the air and enter the food production chain as contaminants. Ingestion of nano- and microplastics present in food and drinking water, or those present in swallowed lung mucus that contain trapped particles, represent the main route of human exposure. Yet much remains to be studied on the intestinal uptake by humans and the potential this exposure has to result in adverse health effects. Here we review the current knowledge and relate this to lessons learned from the field of nanotoxicology. We discuss how in vitro and in silico approaches can be used to support the risk assessment of nano- and microplastics.
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.
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.
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.
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.
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.
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.