Evaluation of immunologic and intestinal effects in rats administered an E 171-containing diet, a food grade titanium dioxide (TiO2)

Blevins, Lance K.; Crawford, R. J.; Bach, Anthony; Rizzo, Michael D.; Zhou, Jiajun; Henriquez, Joseph E.; Khan, Deena; Sermet, Sera; Arnold, Lora L.; Pennington, Karen L.; Souza, Nathália Pereira de; Cohen, Samuel M.; Kaminski, Norbert E.

doi:10.1016/j.fct.2019.110793

Cited by 45 publications

(55 citation statements)

References 79 publications

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“…Recent toxicity studies on TiO 2 raised concerns for liver effects (liver fibrosis, steatosis and edema) (Wang et al 2007, Cui et al 2011, Wang et al 2013, Shukla et al 2014, Azim et al 2015, Talamini et al 2019 and for a potential enhancement or promotion of intestinal tumor formation (Urrutia-Ortega et al 2016, Bettini et al 2017, Proquin et al 2018, Talamini et al 2019, after ingestion. On the other hand, there are also toxicity studies showing no effect on liver and intestine, despite prolonged exposure and high doses (NCI 1979, Warheit, Brown, and Donner 2015, Blevins et al 2019. In order to improve the assessment whether such effects occur due to TiO 2 exposure, we moved beyond the traditional toxicological hazard assessment based on morphological, histopathological and clinical observations.…”

Section: Mechanistic Insights In Effects In Liver and Intestine Aftermentioning

confidence: 99%

“…Further details on the dosing, the animals, the TiO 2 used and the observed effects (if any) are provided in the Supplementary Information of Braakhuis et al (2021). Only Bettini et al (2017) and Blevins et al (2019) explicitly applied food-grade TiO 2 (E171), and Warheit, Brown, and Donner (2015) in part of the experiments, but the TiO 2 in some other studies (e.g. NCI 1979 The AOP consist of an initiating event (IE) and key events (KEs) leading to the adverse outcome (AO) (Braakhuis et al 2021).…”

Section: Ndmentioning

confidence: 99%

“…For each study, information on the exposure duration is provided between parentheses ( Mohamed and Hussien (2016); 10: NCI (1979). (Blevins et al 2019). The authors suggested that the differences between studies might be explained by the difference in the administration of TiO 2.…”

Section: Ndmentioning

confidence: 99%

“…Different types of TiO 2 may be absorbed to a different extent, the distribution over and elimination from tissues can vary, whereas also the potency to exert a hazard may differ. Only a limited number of studies in Tables 1-3 explicitly applied food-grade TiO 2 (E171) (Urrutia-Ortega et al 2016, Bettini et al 2017, Proquin et al 2018, Blevins et al 2019, Talamini et al 2019, or at least in part of their experiments (Warheit, Brown, and Donner 2015). The TiO 2 used in some other studies may also be in line with food grade TiO 2 (see the Supplementary Information for details on the TiO 2 used per study).…”

Section: Ndmentioning

confidence: 99%

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Possible effects of titanium dioxide particles on human liver, intestinal tissue, spleen and kidney after oral exposure

et al. 2020

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Recent studies reported adverse liver effects and intestinal tumor formation after oral exposure to titanium dioxide (TiO 2). Other oral toxicological studies, however, observed no effects on liver and intestine, despite prolonged exposure and/or high doses. In the present assessment, we aimed to better understand whether TiO 2 can induce such effects at conditions relevant for humans. Therefore, we focused not only on the clinical and histopathological observations, but also used Adverse Outcome Pathways (AOPs) to consider earlier steps (Key Events). In addition, aiming for a more accurate risk assessment, the available information on organ concentrations of Ti (resulting from exposure to TiO 2) from oral animal studies was compared to recently reported concentrations found in human postmortem organs. The overview obtained with the AOP approach indicates that TiO 2 can trigger a number of key events in liver and intestine: Reactive Oxygen Species (ROS) generation, induction of oxidative stress and inflammation. TiO 2 seems to be able to exert these early effects in animal studies at Ti liver concentrations that are only a factor of 30 and 6 times higher than the median and highest liver concentration found in humans, respectively. This confirms earlier conclusions that adverse effects on the liver in humans as a result of (oral) TiO 2 exposure cannot be excluded. Data for comparison with Ti levels in human intestinal tissue, spleen and kidney with effect concentrations were too limited to draw firm conclusions. The Ti levels, though, are similar or higher than those found in liver, suggesting these tissues may be relevant too.

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Section: Mechanistic Insights In Effects In Liver and Intestine Aftermentioning

confidence: 99%

Section: Ndmentioning

confidence: 99%

Section: Ndmentioning

confidence: 99%

Section: Ndmentioning

confidence: 99%

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Possible effects of titanium dioxide particles on human liver, intestinal tissue, spleen and kidney after oral exposure

et al. 2020

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“…For example, a recent study where growing rats were fed a pelleted diet containing ≈40, 400, or 5000 mg fgTiO 2 kg −1 diet, and then a large range of analyses undertaken, provided no information to confirm that tissues were actually exposed in the study. [27] This makes the suite of "no effect outcomes" that were reported difficult to interpret.…”

mentioning

confidence: 99%

A Murine Oral‐Exposure Model for Nano‐ and Micro‐Particulates: Demonstrating Human Relevance with Food‐Grade Titanium Dioxide

Riedle

Wills

Miniter

et al. 2020

Small

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Human exposure to persistent, nonbiological nanoparticles and microparticles via the oral route is continuous and large scale (1012–1013 particles per day per adult in Europe). Whether this matters or not is unknown but confirmed health risks with airborne particle exposure warns against complacency. Murine models of oral exposure will help to identify risk but, to date, lack validation or relevance to humans. This work addresses that gap. It reports i) on a murine diet, modified with differing concentrations of the common dietary particle, food grade titanium dioxide (fgTiO2), an additive of polydisperse form that contains micro‐ and nano‐particles, ii) that these diets deliver particles to basal cells of intestinal lymphoid follicles, exactly as is reported as a “normal occurrence” in humans, iii) that confocal reflectance microscopy is the method of analytical choice to determine this, and iv) that food intake, weight gain, and Peyer's patch immune cell profiles, up to 18 weeks of feeding, do not differ between fgTiO2‐fed groups or controls. These findings afford a human‐relevant and validated oral dosing protocol for fgTiO2 risk assessment as well as provide a generalized platform for application to oral exposure studies with nano‐ and micro‐particles.

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Titanium Dioxide

Battersby,

Warheit

2023

Patty's Toxicology

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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.

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Evaluation of immunologic and intestinal effects in rats administered an E 171-containing diet, a food grade titanium dioxide (TiO2)

Cited by 45 publications

References 79 publications

Possible effects of titanium dioxide particles on human liver, intestinal tissue, spleen and kidney after oral exposure

Possible effects of titanium dioxide particles on human liver, intestinal tissue, spleen and kidney after oral exposure

A Murine Oral‐Exposure Model for Nano‐ and Micro‐Particulates: Demonstrating Human Relevance with Food‐Grade Titanium Dioxide

Titanium Dioxide

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