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Lung cancer mortality in the European cohort of titanium dioxide workers: a reanalysis of the exposure–response relationship
  1. Irina Guseva Canu1,
  2. Alan Gaillen-Guedy1,
  3. Ahti Antilla2,
  4. Sandrine Charles3,
  5. Sandrine Fraize-Frontier4,
  6. Danièle Luce5,
  7. Damien Martin McElvenny6,7,
  8. Franco Merletti8,
  9. Cecile Michel3,
  10. Eero Pukkala9,10,
  11. Mary K Schubauer-Berigan11,
  12. Kurt Straif12,13,
  13. Pascal Wild1,
  14. David B Richardson14
  1. 1 Department of Occupational and Environmental Health, Unisanté, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
  2. 2 Mass Screening Registry, Finnish Cancer Institute, Helsinki, Finland
  3. 3 REACh-CLP-Endocrine Disruptors Unit, French Agency for Food, Environmental and Occupational Health and Safety, Maisons-Alfort, France
  4. 4 Methodology and Studies Unit, French Agency for Food, Environmental and Occupational Health and Safety, Maisons-Alfort, France
  5. 5 Institut de Recherche en Santé, Environnement et Travail – UMR_S 1085, INSERM, Univerity of Rennes, University of Angers, EHESP, Pointe-à-Pitre, France
  6. 6 Research Group, Institute of Occupational Medicine, Edinburgh, UK
  7. 7 Centre for Occupational and Environmental Health, The University of Manchester, Manchester, UK
  8. 8 Department of Medical Sciences, University of Torino, Torino, Italy
  9. 9 Institute for Statistical and Epidemiological, Finnish Cancer Registry, Helsinki, Finland
  10. 10 Faculty of Social Sciences, Tampere University, Tampere, Finland
  11. 11 Evidence Synthesis and Classification Branch, International Agency for Research on Cancer, CEDEX, France
  12. 12 Global Observatory on Pollution and Health, Schiller Institute for Integrated Science and Society, Boston College, Chestnut Hill, Massachusetts, USA
  13. 13 Department of Non-communicable Diseases and Environment, ISGlobal, Barcelona, Spain
  14. 14 Department of Environmental and Occupational Health, University of California, Irvine, California, USA
  1. Correspondence to Professor Irina Guseva Canu, Department of Occupational and Environmental Health, Unisanté, University of Lausanne Faculty of Biology and Medicine, 1066 Lausanne, Vaud, Switzerland; irinacanu{at}


Objectives Animal bioassays have demonstrated convincing evidence of the potential carcinogenicity to humans of titanium dioxide (TiO2), but limitations in cohort studies have been identified, among which is the healthy worker survivor effect (HWSE). We aimed to address this bias in a pooled study of four cohorts of TiO2 workers.

Methods We reanalysed data on respirable TiO2 dust exposure and lung cancer mortality among 7341 male workers employed in TiO2 production in Finland, France, UK and Italy using the parametric g-formula, considering three hypothetical interventions: setting annual exposures at 2.4 (U.S. occupational exposure limit), 0.3 (German limit) and 0 mg/m3 for 25 and 35 years.

Results The HWSE was evidenced. Taking this into account, we observed a positive association between lagged cumulative exposure to TiO2 and lung cancer mortality. The estimated number of lung cancer deaths at each age group decreased across increasingly stringent intervention levels. At age 70 years, the estimated number of lung cancer deaths expected in the cohort after 35-year exposure was 293 for exposure set at 2.4 mg/m3, 235 for exposure set at 0.3 mg/m3, and 211 for exposure set at 0 mg/m3.

Conclusion This analysis shows that HWSE can hide an exposure–response relationship. It also shows that TiO2 epidemiological data could demonstrate an exposure–effects relationship if analysed appropriately. More epidemiological studies and similar reanalyses of existing cohort studies are warranted to corroborate the human carcinogenicity of TiO2. This human evidence, when combined with the animal evidence, strengthens the overall evidence of carcinogenicity of TiO2.

  • Occupational Health
  • Lung Diseases, Interstitial
  • Statistics as Topic
  • Longitudinal studies
  • Dust

Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study. Not applicable.

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Data availability statement

Data sharing not applicable as no datasets generated and/or analysed for this study. Not applicable.

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  • Contributors IGC designed and conducted this study and drafted the manuscript, AG-G, DR and PW conducted statistical analyses. KS and MS-B centralised the data, facilitated data access, and obtained IARC ethical approval. SC, SF-F and CM contributed to study coordination and French ethical approval. All authors discussed the study methodology, read the manuscript, critically reviewed it and agreed on the final version.

  • Funding This work was supported by the ANSES, Grant number ANSES/IST 2017-CRD-18.

  • Disclaimer Where authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/WHO.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.