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

Abstract

ObjectivesTitanium dioxide (TiO2) is widely used in construction, food, cosmetic and medical industry. The current evidence on TiO2 carcinogenicity in humans is considered inadequate. As French participants of the European cohort of TiO2 workers exhibited an increase in mortality from lung cancer, we aimed at investigating whether TiO2 exposure, co-exposures or smoking can explain this increase.MethodsWe 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 TiO2 dust as primary exposure of interest, estimated as continuous cumulative (mg/m3-year) and annual average (mg/m3) concentrations and binary and 4-class categorical variables, with cut-off values of 0.3 and 2.4 mg/m3 (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.ResultsThe fully adjusted model yielded a HR=3.7 (95% CI=0.79 to 17.95) for TiO2-exposed workers vs unexposed and a HR=27.33 (95% CI=4.35 to 171.84) for those exposed to >2.4 mg/m3 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/m3-year).ConclusionThis study suggests a positive relationship between TiO2 exposure and lung cancer mortality in TiO2 workers, whatever the exposure variable used, despite a limited statistical power in some models. The results question the current evidence on TiO2 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

“…Prior to undertaking the g-formula analysis, we assessed the most important HWSE components in these data and confirmed their presence. Moreover, prior reports of SMR analyses indicated patterns consistent with the HWSE3 and in the analysis of the French cohort, duration of employment was negatively associated with lung cancer mortality 2. These underscore the relevance of g-methods in these cohorts and future investigations of TiO 2 ’s effects on human health.…”

“…The exchangeability assumption (ie, no unmeasured confounding) is challenging given the limitations of available data on smoking. The most complete smoking data were available for the French cohort and showed no effect of adjustment for smoking on estimates of TiO 2 -lung cancer mortality associations 2. Moreover, we were able to assess some other occupational coexposures that are suspected or known lung carcinogens, including asbestos, welding fumes and other mineral dusts; adjustment for these exposures had no effect on the association with TiO 2 .…”

“…Prior large cohorts of TiO 2 workers reported increased mortality from lung cancer, but failed to observe an exposure–response relationship with cumulative exposure to TiO 2 ,1 except in a French cohort of TiO 2 workers 2. One of the key limitations noted in the occupational cohorts was the potential healthy worker survivor effect (HWSE), which can mask association between cumulative exposure and lung cancer mortality 3.…”

Response to Tomenson’s letter on ‘Lung cancer mortality in the French cohort of titanium dioxide workers: some aetiological insights’

“…Obviously, this also affects the number of unexposed and exposed workers as reported in the supplemental Table S3. 2 We recognize that we should have specified this also in the footnotes of that table.Regarding tobacco smoking, data were available for 201 (not only 33) workers at the second French plant and the combined crude smoking prevalence for the two French plants was 34%, compatible with the age-standardized prevalence of 42% reported by Boffetta et al 1 As discussed in our paper, 2 we recognize that the reported prevalence of smoking was low, and lower than that estimated on the national level.…”

“…Obviously, this also affects the number of unexposed and exposed workers as reported in the supplemental Table S3. 2 We recognize that we should have specified this also in the footnotes of that table.…”