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

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.

Weight of epidemiological evidence for titanium dioxide risk assessment: current state and further needs.

We address here the importance of epidemiological evidence in risk assessment and decision-making in Europe. To illustrate this, titanium dioxide (TiO2) was used as a model compound. TiO2 is widely used as an odorless white pigment and opacifying agent. A recent systematic review assessing the weight of evidence on the relationship between exposure to TiO2 (all forms) and cancer in humans questions the assumptions that TiO2 is an inert material of low toxicity. Based on this new data, France submitted a proposal to classify TiO2 as a possible human carcinogen under the European regulation. The European Chemicals Agency Risk assessment committee concluded that TiO2 (all forms) warrants a classification as a suspected human carcinogen via inhalation (Category-2) under the CLP regulation (for Classification, Labeling and Packaging of chemicals). No considerations was given to TiO2 particle size, which may affect human health effects. Consequently, further epidemiological studies are needed to assess possible associations between different physical-chemical characteristics of TiO2 exposures and their impact on human health. This would allow strengthening the evidence on which to build the most appropriate regulation and to guaranty safe use given any exposure route of any TiO2 particle shape or size.

Experiencing a probabilistic approach to clarify and disclose uncertainties when setting occupational exposure limits.

OBJECTIVES: Assessment factors (AFs) are commonly used for deriving reference concentrations for chemicals. These factors take into account variabilities as well as uncertainties in the dataset, such as inter-species and intra-species variabilities or exposure duration extrapolation or extrapolation from the lowest-observed-adverse-effect level (LOAEL) to the noobserved- adverse-effect level (NOAEL). In a deterministic approach, the value of an AF is the result of a debate among experts and, often a conservative value is used as a default choice. A probabilistic framework to better take into account uncertainties and/or variability when setting occupational exposure limits (OELs) is presented and discussed in this paper. MATERIAL AND METHODS: Each AF is considered as a random variable with a probabilistic distribution. A short literature was conducted before setting default distributions ranges and shapes for each AF commonly used. A random sampling, using Monte Carlo techniques, is then used for propagating the identified uncertainties and computing the final OEL distribution. RESULTS: Starting from the broad default distributions obtained, experts narrow it to its most likely range, according to the scientific knowledge available for a specific chemical. Introducing distribution rather than single deterministic values allows disclosing and clarifying variability and/or uncertainties inherent to the OEL construction process. CONCLUSIONS: This probabilistic approach yields quantitative insight into both the possible range and the relative likelihood of values for model outputs. It thereby provides a better support in decision-making and improves transparency. Int J Occup Med Environ Health 2018;31(4):475-489.

Is the fresh water fish consumption a significant determinant of the internal exposure to perfluoroalkylated substances (PFAS)?

PFAS are man-made compounds that are highly spread in the environment. Human dietary exposure to such contaminants is of high concern as they may accumulate in the food chain. Different studies already demonstrated the importance of the fish consumption in the dietary exposure of these molecules and the potential increase of internal doses of PFAS following the consumption of PFAS. However, so far few study aimed to study the link between the consumption of fresh water fishes and the internal exposure to PFAS. Objectives of this study were (i) to estimate the internal exposure of populations that are potentially high consumers of fresh water fishes and (ii) to determine whether the consumption of fish caught from fresh water is a significant determinant of the internal exposure of PFAS. In this work, a large sample of adult freshwater anglers from the French metropolitan population (478 individuals) was constituted randomly from participants lists of anglers associations. Questionnaires provided social and demographic information and diet information for each subject. In addition, analyses of blood serum samples provided the internal concentration of 14 PFAS. The survey design allowed to extrapolate the data obtained on the 478 individuals to the freshwater angler population. Descriptive data regarding internal levels of PFAS were discussed at the population level, whereas identification of the determinants were done at the 478 individuals level as sufficient contrast was required in terms of fresh water fish consumption. Only molecules for which the detection frequency were above 80% in blood were considered, i.e., PFOS, PFOA, PFHxS, PFNA, PFHpS, and PFDA. Distribution profiles showed log-normal distribution and PFOS and PFOA were the main contributors of the PFAS sum. For PFOS, the results obtained on the 478 individuals showed that upper percentiles were higher as compared to upper percentiles obtained on occidental general population. This confirmed an over-exposure of a fraction of the 478 individuals. Though, when the results were considered at the population level, the values were close. This was attributed to the low consumption frequency of fresh water fish in the general population. For PFOS, PFNA, PFHxS, PFHpS and PFDA, the fresh water fish consumption was identified as one of the contributors of internal PFAS concentrations. Gender, age, geographical location and consumption of home-grown products as other determinants were also discussed in this paper.