Weight of epidemiological evidence for titanium dioxide risk assessment: current state and further needs

Abstract

We address here the importance of epidemiological evidence in risk assessment and decision-making in Europe. To illustrate this, titanium dioxide (TiO2) was used as a model compound. TiO2 is widely used as an odorless white pigment and opacifying agent. A recent systematic review assessing the weight of evidence on the relationship between exposure to TiO2 (all forms) and cancer in humans questions the assumptions that TiO2 is an inert material of low toxicity. Based on this new data, France submitted a proposal to classify TiO2 as a possible human carcinogen under the European regulation. The European Chemicals Agency Risk assessment committee concluded that TiO2 (all forms) warrants a classification as a suspected human carcinogen via inhalation (Category-2) under the CLP regulation (for Classification, Labeling and Packaging of chemicals). No considerations was given to TiO2 particle size, which may affect human health effects. Consequently, further epidemiological studies are needed to assess possible associations between different physical–chemical characteristics of TiO2 exposures and their impact on human health. This would allow strengthening the evidence on which to build the most appropriate regulation and to guaranty safe use given any exposure route of any TiO2 particle shape or size.

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References

  1. 1.

    Deener K, Sacks JD, Kirrane EF, Glenn EF, Gwinn M, Bateson T, et al. Epidemiology: a foundation of environmental decision making. J Expo Sci Environ Epidemiol. 2018;28:515–21.

    Article  Google Scholar 

  2. 2.

    IARC. Titanium dioxide. IARC monographes on the evaluation of carcinogenic risk to humans: carbon black, titanium dioxide, and talc. vol. 93. Lyon: IARC; 2010. p. 194–276.

  3. 3.

    US-NIOSH. Current Intelligence Bulletin 63. Occupational exposure to titanium dioxide. Cincinnati: Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health; 2011. 140pp.

  4. 4.

    Grande F, Tucci P. Titanium dioxide nanoparticles: a risk for human health? Mini Rev Med Chem. 2016;16:762–9.

    CAS  Article  Google Scholar 

  5. 5.

    Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Cogliano V. Carcinogenicity of carbon black, titanium dioxide, and talc. Lancet Oncol. 2006;7:295–6.

    Article  Google Scholar 

  6. 6.

    ANSES. Proposal for Harmonized classification and labelling based on Regulation (EC) No. 1272/2008 (CLP regulation), Annex VI, Part 2. Substance Name: Titanium dioxide. Maisons-Alfort: ANSES (on behalf of the French MSCA); 2017.

  7. 7.

    Regulation No. 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006. Official J Eur Union. 2008;353:1.

  8. 8.

    Martin P, Bladier C, Meek B, Bruyere O, Feinblatt E, Touvier M, et al. Weight of evidence for hazard identification: a critical review of the literature. Environ Health Perspect. 2018;127:1–15.

    Google Scholar 

  9. 9.

    OHAT. (Office of Health Assessment and Translation) Handbook for conducting a literature-based health assessment using OHAT approach for systematic review and evidence integration. Research Triangle Park, NC: OHAT; 2015.

  10. 10.

    Ellis ED, Watkins J, Tankersley W, Phillips J, Girardi D. Mortality among titanium dioxide workers at three DuPont plants. J Occup Environ Med. 2010;52:303–9.

    CAS  Article  Google Scholar 

  11. 11.

    Ellis ED, Watkins JP, Tankersley WG, Phillips JA, Girardi DJ. Occupational exposure and mortality among workers at three titanium dioxide plants. Am J Ind Med. 2013;56:282–91.

    Article  Google Scholar 

  12. 12.

    Boffetta P, Soutar A, Cherrie JW, Granath F, Andersen A, Anttila A, et al. Mortality among workers employed in the titanium dioxide production industry in Europe. Cancer Causes Control. 2004;15:697–706.

    Article  Google Scholar 

  13. 13.

    Chen JL, Fayerweather WE. Epidemiologic study of workers exposed to titanium dioxide. J Occup Med. 1988;30:937–42.

    CAS  Article  Google Scholar 

  14. 14.

    Fryzek JP, Chadda B, Marano D, White K, Schweitzer S, McLaughlin JK, et al. A cohort mortality study among titanium dioxide manufacturing workers in the United States. J Occup Environ Med. 2003;45:400–9.

    CAS  Article  Google Scholar 

  15. 15.

    Boffetta P, Gaborieau V, Nadon L, Parent MF, Weiderpass E, Siemiatycki J. Exposure to titanium dioxide and risk of lung cancer in a population-based study from Montreal. Scand J Work Environ Health. 2001;27:227–32.

    CAS  Article  Google Scholar 

  16. 16.

    Ramanakumar AV, Parent ME, Latreille B, Siemiatycki J. Risk of lung cancer following exposure to carbon black, titanium dioxide and talc: results from two case-control studies in Montreal. Int J Cancer. 2008;122:183–9.

    CAS  Article  Google Scholar 

  17. 17.

    Arrighi HM, Hertz-Picciotto I. The evolving concept of the healthy worker survivor effect. Epidemiology. 1994;5:189–96.

    CAS  Article  Google Scholar 

  18. 18.

    Richardson D, Wing S, Steenland K, McKelvey W. Time-related aspects of the healthy worker survivor effect. Ann Epidemiol. 2004;14:633–9.

    Article  Google Scholar 

  19. 19.

    ECHA. Titanium dioxide proposed to be classified as suspected of causing cancer when inhaled 2017 [updated 09.06.2017. Available from: https://echa.europa.eu/fr/-/titanium-dioxide-proposed-to-be-classified-as-suspected-of-causing-cancer-when-inhaled.

  20. 20.

    Naimi AI, Cole SR, Kennedy EH. An introduction to g methods. Int J Epidemiol. 2017;46:756–62.

    Article  Google Scholar 

  21. 21.

    Fortier I, Raina P, Van den Heuvel ER, Griffith LE, Craig C, Saliba M, et al. Maelstrom Research guidelines for rigorous retrospective data harmonization. Int J Epidemiol. 2017;46:103–5.

    PubMed  Google Scholar 

  22. 22.

    Grellier J, Atkinson W, Berard P, Bingham D, Birchall A, Blanchardon E, et al. Risk of lung cancer mortality in nuclear workers from internal exposure to alpha particle-emitting radionuclides. Epidemiology. 2017;28:675–84.

    Article  Google Scholar 

  23. 23.

    Guseva Canu I, Garsi JP, Caer-Lorho S, Jacob S, Collomb P, Acker A, et al. Does uranium induce circulatory diseases? First results from a French cohort of uranium workers. Occup Environ Med. 2012;69:404–9.

    Article  Google Scholar 

  24. 24.

    Zhivin S, Guseva Canu I, Davesne E, Blanchardon E, Garsi JP, Samson E, et al. Circulatory disease in French nuclear fuel cycle workers chronically exposed to uranium: a nested case-control study. Occup Environ Med. 2018;75:270–6.

    Article  Google Scholar 

  25. 25.

    Oberdorster G, Ferin J, Lehnert BE. Correlation between particle size, in vivo particle persistence, and lung injury. Environ Health Perspect. 1994;102(Suppl 5):173–9.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Borm PJ, Schins RP, Albrecht C. Inhaled particles and lung cancer, part B: paradigms and risk assessment. Int J Cancer. 2004;110:3–14.

    CAS  Article  Google Scholar 

  27. 27.

    Sager TM, Kommineni C, Castranova V. Pulmonary response to intratracheal instillation of ultrafine versus fine titanium dioxide: role of particle surface area. Part Fibre Toxicol. 2008;5:17.

    Article  Google Scholar 

  28. 28.

    Warheit DB, Reed KL, Webb TR. Pulmonary toxicity studies in rats with triethoxyoctylsilane (OTES)-coated, pigment-grade titanium dioxide particles: bridging studies to predict inhalation hazard. Exp Lung Res. 2003;29:593–606.

    CAS  Article  Google Scholar 

  29. 29.

    Xue C, Wu J, Lan F, Liu W, Yang X, Zeng F, et al. Nano titanium dioxide induces the generation of ROS and potential damage in HaCaT cells under UVA irradiation. J Nanosci Nanotechnol. 2010;10:8500–7.

    CAS  Article  Google Scholar 

  30. 30.

    Numano T, Xu J, Futakuchi M, Fukamachi K, Alexander DB, Furukawa F, et al. Comparative study of toxic effects of anatase and rutile type nanosized titanium dioxide particles in vivo and in vitro. Asian Pac J Cancer Prev. 2014;15:929–35.

    Article  Google Scholar 

  31. 31.

    Schulte P, Leso V, Niang M, Iavicoli I. Biological monitoring of workers exposed to engineered nanomaterials. Toxicology letters. 2018;298:112–24.

    CAS  Article  Google Scholar 

  32. 32.

    Guseva Canu I, Jacob S, Cardis E, Wild P, Caer S, Auriol B, et al. Uranium carcinogenicity in humans might depend on the physical and chemical nature of uranium and its isotopic composition: results from pilot epidemiological study of French nuclear workers. Cancer Causes Control. 2011;22:1563–73.

    CAS  Article  Google Scholar 

  33. 33.

    Couch JR, Petersen M, Rice C, Schubauer-Berigan MK. Development of retrospective quantitative and qualitative job-exposure matrices for exposures at a beryllium processing facility. Occup Environ Med. 2011;68:361–5.

    CAS  Article  Google Scholar 

  34. 34.

    Guseva Canu I, Faust S, Knieczak E, Carles M, Samson E, Laurier D. Estimating historic exposures at the European gaseous diffusion plants. Int J Hyg Environ Health. 2013;216:499–507.

    CAS  Article  Google Scholar 

  35. 35.

    Guseva Canu I, Schulte PA, Riediker M, Fatkhutdinova L, Bergamaschi E. Methodological, political and legal issues in the assessment of the effects of nanotechnology on human health. J Epidemiol Community Health. 2018;72:148–53.

    Article  Google Scholar 

  36. 36.

    ANSES. Toxicological Reference Value (TRV). Establishment of chronic reference value by inhalation for titanium dioxide under nanoform. Contract No.: Request No. 2017-SA-0162 “TiO2 TRV”. Maison Alfort, France: ANSES; 2018

  37. 37.

    Bermudez E, Mangum JB, Wong BA, Asgharian B, Hext PM, Warheit DB, et al. Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicological Sci. 2004;77:347–57.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This work was funded by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES), Grant No. D 17LESCO410.

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Correspondence to Irina Guseva Canu.

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Guseva Canu, I., Fraize-Frontier, S., Michel, C. et al. Weight of epidemiological evidence for titanium dioxide risk assessment: current state and further needs. J Expo Sci Environ Epidemiol 30, 430–435 (2020). https://doi.org/10.1038/s41370-019-0161-2

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Keywords

  • Lung cancer
  • Nanoparticle
  • Systematic review
  • Occupational exposure
  • Bias
  • Policy

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