Lung cancer mortality in the French cohort of titanium dioxide workers: some aetiological insights.

Titanium dioxide (TiO <sub>2</sub> ) is widely used in construction, food, cosmetic and medical industry. The current evidence on TiO <sub>2</sub> carcinogenicity in humans is considered inadequate. As French participants of the European cohort of TiO <sub>2</sub> workers exhibited an increase in mortality from lung cancer, we aimed at investigating whether TiO <sub>2</sub> exposure, co-exposures or smoking can explain this increase. We reanalysed the data of 833 French male workers (follow-up period 1968-1997) and used multiple imputation to complete their smoking status. We considered respirable TiO <sub>2</sub> dust as primary exposure of interest, estimated as continuous cumulative (mg/m <sup>3</sup> -year) and annual average (mg/m <sup>3</sup> ) concentrations and binary and 4-class categorical variables, with cut-off values of 0.3 and 2.4 mg/m <sup>3</sup> (the German and American occupational exposure limits, respectively). For each exposure metric, we estimated HRs and associated 95% CIs, using Cox regression models adjusted for calendar period, exposure duration and smoking. The fully adjusted model yielded a HR=3.7 (95% CI=0.79 to 17.95) for TiO <sub>2</sub> -exposed workers vs unexposed and a HR=27.33 (95% CI=4.35 to 171.84) for those exposed to >2.4 mg/m <sup>3</sup> as annual average concentration. Employment duration was negatively related with lung cancer mortality, therefore cumulative exposure had a small effect on mortality (HR=1.03 (95% CI=0.99 to 1.08) per mg/m <sup>3</sup> -year). This study suggests a positive relationship between TiO <sub>2</sub> exposure and lung cancer mortality in TiO <sub>2</sub> workers, whatever the exposure variable used, despite a limited statistical power in some models. The results question the current evidence on TiO <sub>2</sub> carcinogenicity in humans but need to be confirmed in other cohorts, using different statistical approaches

Lung cancer mortality in the European cohort of titanium dioxide workers: a reanalysis of the exposure-response relationship.

Animal bioassays have demonstrated convincing evidence of the potential carcinogenicity to humans of titanium dioxide (TiO <sub>2</sub> ), 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 TiO <sub>2</sub> workers. We reanalysed data on respirable TiO <sub>2</sub> dust exposure and lung cancer mortality among 7341 male workers employed in TiO <sub>2</sub> 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/m <sup>3</sup> for 25 and 35 years. The HWSE was evidenced. Taking this into account, we observed a positive association between lagged cumulative exposure to TiO <sub>2</sub> 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/m <sup>3</sup> , 235 for exposure set at 0.3 mg/m <sup>3</sup> , and 211 for exposure set at 0 mg/m <sup>3</sup> . This analysis shows that HWSE can hide an exposure-response relationship. It also shows that TiO <sub>2</sub> 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 TiO <sub>2</sub> . This human evidence, when combined with the animal evidence, strengthens the overall evidence of carcinogenicity of TiO <sub>2</sub>