Systematic Review of the Mechanistic Evidence for TiO2 NP Lung Carcinogenicity

Details

• Personal Author:
  Bing HL ; Camassa LM ; Mohr B ; Pathak D ; Samulin-Erdem J ; Sriram K ; Wolf S ; Zienolddiny-Narui S
• Description:
  Background and Purpose: Titanium dioxide nanoparticles (TiO2 NP) are a high production volume material widely used in the paints, cosmetic, food and photovoltaics industry. Their increasing industrial demand and use raises concerns of adverse human exposure and related health effects. Epidemiological and animal studies suggest that TiO2 elicits cancer development and consequently is classified as possibly carcinogenic to humans (Group 2B) by the International Agency for Research on Cancer. However, the mechanistic basis of TiO2 NP-mediated lung carcinogenicity is not clear. Here, we systematically reviewed literature to identify in vitro and in vivo mechanistic evidence of TiO2 NP lung carcinogenicity using the 10 key characteristics (KC) of carcinogens for identifying and classifying carcinogens. Methods: Based on the 'Population, Exposure, Comparator, Outcome and Study' framework, a systematic literature search of studies published between 2006 and 2023 was performed using the four databases PubMed, Embase, Web of Science and TOXicology information onLINE to identify existing in vitro and in vivo data on the mechanisms of TiO2 NP toxicity relevant to the onset of lung carcinogenicity. The 10 KC of carcinogens were comprised in the following six search strings: 'Genotoxicity', 'Oxidative stress', 'Chronic inflammation', 'Epigenetic effects', 'Proliferation, Apoptosis' and 'Receptor-mediated effects'. Two independent reviewers did the title/abstract and full-text screening by applying predefined inclusion and exclusion criteria. The quality and reliability of the studies was assessed by using the ToxRTool, which resulted in the assignment of modified Klimisch scores. Studies receiving a Klimisch score 1 or 2 were eligible for data extraction which followed standardized forms and guidelines. Finally, a weight-of-evidence approach was used to evaluate the assays/endpoints investigated to study the respective KC in terms of their association with carcinogenic hazard. Results: The systematic literature search yielded a total of 15,489 articles, which were screened for title/abstract and 1,842 articles were assessed for eligibility in the full-text screening. After curating the reference database (i.e., removal of overlapping studies in the six search strings), 346 articles were included in the quality and reliability assessment using the ToxRTool, of which 262 articles reported in vitro data and 102 articles reported in vivo data. Of these, 186 articles were considered of good quality and provided moderate to high level of confidence for the biological endpoints examined. Our analysis showed limited availability of mechanistic data related to carcinogenesis, such as proliferation, epigenetic alterations and receptor-mediated effects. There was evidence for genotoxicity, oxidative stress and chronic inflammation following TiO2 NP exposure. However, the wide variety of TiO2 NP used in the studies, differing in their physicochemical characteristics, methods of formulation, exposure scenarios/test systems, and experimental protocols made it very challenging to compare the studies. Conclusions: Future toxicology/ carcinogenicity research must include appropriate positive controls, endotoxin testing, statistical power analysis, and relevant biological endpoints, to improve the quality and reliability of the studies to be useful for the evaluation of TiO2 NP-induced lung carcinogenicity. There is clearly a need for more physiologically relevant, long-term studies using appropriate particle doses. The limited quality of currently available evidence constrains us from drawing a conclusion that pulmonary exposure to TiO2 NP induces lung cancer. [Description provided by NIOSH]
• Subjects:
  Carcinogens Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety Titanium Toxicology
• Keywords:
  Carcinogenicity In Vitro Studies In Vivo Studies Lung Cancer Nanoparticles Nanotoxicology Titanium Dioxide
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  73-74
• Volume:
  198
• NIOSHTIC Number:
  nn:20069317
• Citation:
  Toxicologist 2024 Mar; 198(S1):73-74
• CAS Registry Number:
  Titania (CAS RN 13463-67-7)
• Federal Fiscal Year:
  2024
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 63rd Annual Meeting & ToxExpo, March 10-14, 2024, Salt Lake City, Utah
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:5bbdf85c2dbc478561bbf966bd16d776d9d81731ed01de9662dfd1103053e93e60e61a2adaf7c78c9c6aedee82e44d339c3268f5f0fe990c27a40abc928e4ef2
• Download URL:
  https://stacks.cdc.gov/view/cdc/207817/cdc_207817_DS1.pdf
• File Type:
  [PDF - 575.76 KB ]