Development of linear and threshold no significant risk levels for inhalation exposure to titanium dioxide using systematic review and mode of action considerations

Thompson, Chad M.; Suh, Mina; Mittal, Liz; Wikoff, Daniele; Welsh, Brian T.; Proctor, Deborah M.

doi:10.1016/j.yrtph.2016.05.031

Cited by 16 publications

(12 citation statements)

References 39 publications

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“…In assessments supporting regulation in the United States, most have estimated the carcinogenic risk at low doses by using LNT, with the exception of the EPA's assessment of chloroform [EPA 2001]. In contrast, others have used a PoD/UF approach to derive safe levels for non-genotoxic and some genotoxic carcinogens [Bevan and Harrison 2017;Kirman et al 2016;Pecquet et al 2018;Seeley et al 2001;Thompson et al 2016…”

Section: Carcinogensmentioning

confidence: 99%

Current intelligence bulletin 69: NIOSH practices in occupational risk assessment.

Daniels¹,

Gilbert²,

Kuppusamy³

et al. 2020

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This document is in the public domain and may be freely copied or reprinted. Disclaimer Mention of any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention. In addition, citations to websites external to NIOSH do not constitute NIOSH endorsement of the sponsoring organizations or their programs or products. Furthermore, NIOSH is not responsible for the content of these websites. All web addresses referenced in this document were accessible as of the publication date.

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Section: Carcinogensmentioning

confidence: 99%

Current intelligence bulletin 69: NIOSH practices in occupational risk assessment.

Daniels¹,

Gilbert²,

Kuppusamy³

et al. 2020

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“…The availability of a non-cancer RfD already derived for hyperplasia (Wikoff et al, 2015) and the proximity of that RfD to our RfD cancer for the (2017) uterine tumor outcome is reassuring, and further supports the threshold mechanism. Thompson et al (2016) used a precursor effect to derive an NSRL for titanium dioxide; however, there are extensive MOA data for this chemical and an available and fully vetted adverse outcome pathway for this tumor endpoint. Their ability to use a defined precursor likely stems from the vast amount of available data.…”

Section: Uncertaintiesmentioning

confidence: 99%

“…This determination affects the choice of either the derivation of a cancer slope factor and a risk-specific dose, or a threshold-based toxicity reference value for cancer effects (RfD cancer ). Accordingly, two recent NSRLs were developed for diethanolamine (Kirman, Hughes, Becker, & Hays, 2016) and titanium dioxide (Thompson et al, 2016) using threshold approaches based on non-mutagenic MOAs.…”

mentioning

confidence: 99%

Derivation of a no‐significant‐risk‐level for tetrabromobisphenol A based on a threshold non‐mutagenic cancer mode of action

Pecquet

Martinez

Vincent

et al. 2018

J of Applied Toxicology

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A no‐significant‐risk‐level of 20 mg day–1 was derived for tetrabromobisphenol A (TBBPA). Uterine tumors (adenomas, adenocarcinomas, and malignant mixed Müllerian) observed in female Wistar Han rats from a National Toxicology Program 2‐year cancer bioassay were identified as the critical effect. Studies suggest that TBBPA is acting through a non‐mutagenic mode of action. Thus, the most appropriate approach to derivation of a cancer risk value based on US Environmental Protection Agency guidelines is a threshold approach, akin to a cancer safe dose (RfDcancer). Using the National Toxicology Program data, we utilized Benchmark dose software to derive a benchmark dose lower limit (BMDL10) as the point of departure (POD) of 103 mg kg–1 day–1. The POD was adjusted to a human equivalent dose of 25.6 mg kg–1 day–1 using allometric scaling. We applied a composite adjustment factor of 100 to the POD to derive an RfDcancer of 0.26 mg kg–1 day–1. Based on a human body weight of 70 kg, the RfDcancer was adjusted to a no‐significant‐risk‐level of 20 mg day–1. This was compared to other available non‐cancer and cancer risk values, and aligns well with our understanding of the underlying biology based on the toxicology data. Overall, the weight of evidence from animal studies indicates that TBBPA has low toxicity and suggests that high doses over long exposure durations are needed to induce uterine tumor formation. Future research needs include a thorough and detailed vetting of the proposed adverse outcome pathway, including further support for key events leading to uterine tumor formation and a quantitative weight of evidence analysis.

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“…There are many types of TiO 2 depending on the combination of particle size, crystal structures, and surface modification. TiO 2 occurs in nature in three mineral crystal structures: anatase, rutile, and brookite [3, 4]. A lot of progress has been made in development of technology for surface processing of TiO 2 particles to give them additional characteristics [5].…”

Section: Introductionmentioning

confidence: 99%

Lack of pulmonary fibrogenicity and carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model

Yamano

Takeda

Goto

et al. 2021

Preprint

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Background: With the rapid development of alternative methods based on the spirit of animal welfare, the publications of animal studies evaluating endpoints such as cancer have been extremely reduced. There have been no systemic inhalation exposure studies of titanium dioxide nanoparticles (TiO2 NPs) using CByB6F1-Tg(HRAS)2Jic (rasH2) 26-week study mice model for detecting carcinogenicity. Methods: Male and female rasH2 mice were exposed to 2, 8 or 32 mg/m3 of TiO2 NPs for 6 hours/day, 5 days/week for 26 weeks using a whole-body inhalation exposure system, with reference to the Organization for Economic Co-operation and Development principles of Good Laboratory Practice. All tissues including lungs, and blood were collected and subjected to biological and histopathological analyses. Additionally, Ki67 positive index were evaluated in mice lung alveolar epithelial type 2 cell (AEC2). Results: This study established a stable method for generating and exposing TiO2 NPs aerosol, and clarified the dose-response relationship by TiO2 NPs inhalation to rasH2 mice. TiO2 NPs exposure induced deposition of particles in lungs and mediastinal lymph nodes in a dose-dependent manner in each exposure group. Additionally, alveolar inflammation was only observed in 32 mg/m3 exposure group in both the sexes. Exposure to TiO2 NPs, as well as other organs, did not increase the incidence of lung tumors in any group, and pulmonary fibrosis and pre-neoplastic lesions were not observed in all groups. Finally, the cell proliferative activity of AEC2 was examined, and it was not increased by exposure to TiO2 NPs. Conclusions: This is the first report showing the lack of pulmonary fibrogenicity and carcinogenicity (no evidence of carcinogenic activity) of TiO2 NPs in 26-week inhalation study in rasH2 mice exposed up to 32 mg/m3, which is considered to be a high concentration. Macrophages undergoing phagocytosis due to TiO2 NPs exposure formed inflammatory foci in the alveolar regions of exposed mice but did not develop fibrosis or hyperplasia or tumors. Moreover, the cell proliferative ability of AEC2 in lesions was not increased. In addition, no carcinogenicity was observed for any organs other than the lungs in this study.

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Development of linear and threshold no significant risk levels for inhalation exposure to titanium dioxide using systematic review and mode of action considerations

Cited by 16 publications

References 39 publications

Current intelligence bulletin 69: NIOSH practices in occupational risk assessment.

Current intelligence bulletin 69: NIOSH practices in occupational risk assessment.

Derivation of a no‐significant‐risk‐level for tetrabromobisphenol A based on a threshold non‐mutagenic cancer mode of action

Lack of pulmonary fibrogenicity and carcinogenicity of titanium dioxide nanoparticles in 26-week inhalation study in rasH2 mouse model

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