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

Journal of Exposure Science & Environmental Epidemiology volume 32, pages 493–494 (2022)Cite this article

Guseva Canu et al. [1] performed what they describe as a weight of evidence (WOE) assessment of TiO2 carcinogenicity in humans, although no attempt was made to integrate evidence from different studies. Furthermore, the authors claimed to have followed guidelines prescribed by a review [2] which clearly identified evidence integration as the 3rd of 4 steps of a WOE assessment. The “WOE” assessment only included: (i) a literature search; (ii) a standardised evaluation of key aspects of each selected study; and (iii) an analysis of the risk for bias according to the OHAT approach [3]. However, the inclusion of studies and their findings is very selective, and the paper demonstrates a poor understanding of the types of bias to be included in an OHAT assessment, and the OHAT risk of bias rating tool. For example, Table S1 of Guseva Canu et al. [1] discusses performance bias, but Table 5 of the OHAT handbook [3] indicates that this bias is only relevant for experimental animal studies or studies in humans with a controlled exposure, and not cohort or case-control studies. The performance bias section of Table S1 not only discusses study power which is not relevant to risk of bias (it is noted that inclusion/exclusion criteria may have resulted in a loss of power for all studies), but also includes discussion of types of bias such as selection, confounding and detection that should have been included in the appropriate section of the OHAT risk of bias assessment. Furthermore, Guseva Canu et al. [1] did not rate the risk of all seven relevant types of bias. Simply listing the amount of smoking information available for a study, or the source of funding, is not equivalent to rating the risk of confounding or selective reporting bias. In addition, the risk of bias was not assessed at the outcome level as specified by OHAT risk of bias rating tool. For example, an exposure-response analysis will usually have a much lower risk of selection bias than an external mortality or incidence comparison.

The cut-off date for the literature search was 31st of August 2015 which is surprising in a paper submitted for publication in March 2019, but also meant that another WOE assessment of TiO2 carcinogenicity utilising the OHAT approach [4] and a meta-analysis which reported new exposure-response analyses [5] were not included. The WOE assessment [4] concluded that the human data did not provide evidence of a dose response relationship. The meta-analysis [5] combined results from the three key industry-based cohort studies [6,7,8] which in total included more than 24,000 TiO2 production workers. For lung cancer, the summary standardised mortality ratio was 1.10 (95% CI 0.91–1.32), but an association with occupational exposure to TiO2 was not suggested by the summary hazard ratio of 0.999 (95% CI 0.997–1.002) for a 1 mg/m3 year increase in cumulative TiO2 exposure. In addition, two population case control studies [9, 10] which showed no evidence of an association between lung cancer and TiO2 exposure were excluded on the weak premise that they “included a broad array of workers not specifically exposed to TiO2”.

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    John Andrew Tomenson

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Tomenson, J.A. Re: Weight of epidemiological evidence for titanium dioxide risk assessment: current state and further needs. J Expo Sci Environ Epidemiol 32, 493–494 (2022). https://doi.org/10.1038/s41370-021-00341-5

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