Developmental toxicity studies with 6 forms of titanium dioxide test materials (3 pigment-different grade &amp; 3 nanoscale) demonstrate an absence of effects in orally-exposed rats

Warheit, David B.; Boatman, Rodney J.; Brown, Scott C.

doi:10.1016/j.yrtph.2015.09.032

Cited by 35 publications

(30 citation statements)

References 17 publications

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“…Other recent oral reprotoxicity guideline studies performed with rabbits observed no effects after exposure to six different well-characterized TiO 2 materials, including pigments and fully nano-sized TiO 2 (Warheit et al, 2015b). These studies focused on developmental toxicity, and do not cover the reproductive organ toxicity effects reported by Jia et al (2014) and Tassinari et al (2014).…”

Section: Kinetic Modelmentioning

confidence: 97%

“…These studies focused on developmental toxicity, and do not cover the reproductive organ toxicity effects reported by Jia et al (2014) and Tassinari et al (2014). Developmental toxicity studies, such as the ones of Warheit et al (2015b), do not analyze hormone levels and organ histopathology, for example, and only dose female rats that are already pregnant from gestation day 5 onwards. Effects of a substance on the ability to become pregnant are thus not investigated in these studies.…”

Section: Kinetic Modelmentioning

confidence: 99%

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Risk assessment of titanium dioxide nanoparticles via oral exposure, including toxicokinetic considerations

et al. 2016

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Titanium dioxide white pigment consists of particles of various sizes, from which a fraction is in the nano range (5100 nm). It is applied in food as additive E 171 as well as in other products, such as food supplements and toothpaste. Here, we assessed whether a human health risk can be expected from oral ingestion of these titanium dioxide nanoparticles (TiO 2 NPs), based on currently available information. Human health risks were assessed using two different approaches: Approach 1, based on intake, i.e. external doses, and Approach 2, based on internal organ concentrations using a kinetic model in order to account for accumulation over time (the preferred approach). Results showed that with Approach 1, a human health risk is not expected for effects in liver and spleen, but a human health risk cannot be excluded for effects on the ovaries. When based on organ concentrations by including the toxicokinetics of TiO 2 NPs (Approach 2), a potential risk for liver, ovaries and testes is found. This difference between the two approaches shows the importance of including toxicokinetic information. The currently estimated risk can be influenced by factors such as absorption, form of TiO 2 , particle fraction, particle size and physico-chemical properties in relation to toxicity, among others. Analysis of actual particle concentrations in human organs, as well as organ concentrations and effects in liver and the reproductive system after chronic exposure to well-characterized TiO 2 (NPs) in animals are recommended to refine this assessment.

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Section: Kinetic Modelmentioning

confidence: 97%

Section: Kinetic Modelmentioning

confidence: 99%

Risk assessment of titanium dioxide nanoparticles via oral exposure, including toxicokinetic considerations

et al. 2016

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“…Therefore, according to the Panel, further research is needed before the results of this study can be used for risk assessment. Warheit et al (2015a) evaluated three pigment-grade (pg-1, pg-2 and pg-3) and three ultrafine (uf-1, uf-2 and uf-3)/nanoscale (anatase and/or rutile) TiO 2 particulates in prenatal developmental toxicity studies in pregnant rats, according to OECD TG 414. All six test particles contained > 95 wt % TiO 2 .…”

Section: Developmental Toxicity Studiesmentioning

confidence: 99%

Re-evaluation of titanium dioxide (E 171) as a food additive

2016

EFSA Journal

114

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The present Opinion deals with the re-evaluation of the safety of titanium dioxide (TiO 2 , E 171) when used as a food additive. From the available data on absorption, distribution and excretion, the EFSA Panel on Food Additives and Nutrient Sources added to Food concluded that the absorption of orally administered TiO 2 is extremely low and the low bioavailability of TiO 2 appears to be independent of particle size. The Panel concluded that the use of TiO 2 as a food additive does not raise a genotoxic concern. From a carcinogenicity study with TiO 2 in mice and in rats, the Panel chose the lowest no observed adverse effects levels (NOAEL) which was 2,250 mg TiO 2 /kg body weight (bw) per day for males from the rat study, the highest dose tested in this species and sex. The Panel noted that possible adverse effects in the reproductive system were identified in some studies conducted with material which was either non-food-grade or inadequately characterised nanomaterial (i.e. not E 171). There were no such indications in the available, albeit limited, database on reproductive endpoints for the food additive (E 171). The Panel was unable to reach a definitive conclusion on this endpoint due to the lack of an extended 90-day study or a multigeneration or extended-one generation reproduction toxicity study with the food additive (E 171). Therefore, the Panel did not establish an acceptable daily intake (ADI). The Panel considered that, on the database currently available and the considerations on the absorption of TiO 2 , the margins of safety (MoS) calculated from the NOAEL of 2,250 mg TiO 2 /kg bw per day identified in the toxicological data available and exposure data obtained from the reported use/analytical levels of TiO 2 (E 171) would not be of concern. The Panel concluded that once definitive and reliable data on the reproductive toxicity of E 171 were available, the full dataset would enable the Panel to establish a health-based guidance value (ADI).

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“…Consistent with our findings, Warheit et al found that the numbers of implantation sites, early and late resorptions were all comparable to control group values for every dose level tested, which were 0, 100, 300 or 1,000 mg/kg/day TiO 2 NPs in Sprague-Dawley rats from GD 6 through GD 20. 25 The authors concluded that TiO 2 NP exposure produced no evidence of maternal or developmental toxicity at any dose level. However, Zhao et al's study demonstrated that female mice who were exposed to 2.5, 5 and 10 mg/kg TiO 2 NPs by intragastric administration for 90 …”

Section: Discussionmentioning

confidence: 99%

Gestational exposure to titanium dioxide nanoparticles impairs the placentation through dysregulation of vascularization, proliferation and apoptosis in mice

Zhang

Xie

Zhou

et al. 2018

IJN

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Background Titanium dioxide nanoparticles (TiO 2 NPs) have recently found applications in a wide variety of consumer goods. TiO 2 NPs exposure significantly increases fetal deformities and mortality. However, the potential toxicity of TiO 2 NPs on the growth and development of placenta has been rarely studied during mice pregnancy. Purpose The objective of this study was to investigate the effects of maternal exposure of TiO 2 NPs on the placentation. Methods Mice were administered TiO 2 NPs by gavage at 0, 1 and 10 mg/kg/day from gestational day (GD) 1 to GD 13. Uteri and placentas from these mice were collected and counted the numbers of implanted and resorbed embryo and measured the placental weight on GD 13. Placental morphometry was observed by hematoxylin and eosin staining. The levels of Hand1, Esx1 , Eomes , Hand2 , Ascl2 and Fra1 mRNA were assessed by qRT-PCR. Uterine NK (uNK) cells were detected by using DBA lectin. Laminin immunohistochemical staining was to identify fetal vessels. Western blotting and transmission electron micrograph (TEM) were used to assess the apoptosis of placenta. Results No treatment-related difference was observed in the numbers of implanted and resorbed embryos and weight of placenta between the groups. However, 1 mg/kg/day TiO 2 NPs treatment significantly reduced the ratio of placenta/body weight on GD 13. The proportion of spongiotrophoblast in the 10 mg/kg/day dose group became higher than that in the control group, yet that of labyrinth was significantly lower in 10 mg/kg/day mice. The expression levels of Hand1 , Esx1 , Eomes , Hand2 , Ascl2 and Fra1 mRNA markedly decreased in TiO 2 NP treated placentas. Furthermore, TiO 2 NPs treatment impaired the formation of intricate networks of fetal vessels and reduced the number of uNK cells, and inhibited proliferation and induced apoptosis of placenta by nuclear pyknosis, the activation of caspase-3 and upregulation of Bax protein and downregulation of Bcl-2 protein on GD 13. Conclusion Gestational exposure to TiO 2 NPs significantly impairs the growth and development of placenta in mice, with a mechanism that seems to be involved in the dysregulation of vascularization, proliferation and apoptosis. Therefore, our results suggested the need for great caution while handling of the nanomaterials by workers and specially pregnant consumers.

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Developmental toxicity studies with 6 forms of titanium dioxide test materials (3 pigment-different grade & 3 nanoscale) demonstrate an absence of effects in orally-exposed rats

Cited by 35 publications

References 17 publications

Risk assessment of titanium dioxide nanoparticles via oral exposure, including toxicokinetic considerations

Risk assessment of titanium dioxide nanoparticles via oral exposure, including toxicokinetic considerations

Re-evaluation of titanium dioxide (E 171) as a food additive

Gestational exposure to titanium dioxide nanoparticles impairs the placentation through dysregulation of vascularization, proliferation and apoptosis in mice

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