No abstract

No abstract

ObjectivesAnimal 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.MethodsWe 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.ResultsThe 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.ConclusionThis 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.

IntroductionInorganic lead is considered a probable carcinogen by IARC (brain, lung, and stomach).MethodsWe conducted internal analyses via Cox regression of cancer incidence in two cohorts of lead-exposed workers with blood lead data (Finland, UK ), including almost 30 000 workers (20 752 in Finland and 9122 in the UK) and over 10 000 incident cancers. Our exposure metric was maximum annual blood lead (BL) test.ResultsThe combined cohort had a median maximum blood lead of 29 ug/dl, a mean first year BL test of 1977, and was 87% male. Forty-seven percent had more than 1 BL test. Significant (p<0.05) positive trends, using the log of each worker’s maximum BL, were found for brain cancer (malignant and benign combined), Hodgkins’s lymphoma, lung cancer, and rectal cancer, while significant negative trends were found for colon cancer and melanoma. A borderline significant positive trend (0.05≤p≤0.10) was found for esophageal cancer. Significant interactions by country were found only for lung cancer, with Finland showing a strong positive trend and the UK showing only a modest trend. However, in general trends were marked in Finland and weak or inconsistent in the UK.ConclusionsWe found strong positive incidence trends with increasing blood lead level, for several outcomes in internal analysis. Two of these, lung and brain cancer, were a priori suspected sites. Two of these outcomes are associated with smoking (lung and esophageal cancer), for which we had no data; however, we had no a priori reason to believe smoking differed between workers with different BL levels.