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
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.
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