Technical report 122

Titanium dioxide IARC evaluation (2010)

Titanium dioxide IARC evaluation (2010)

There is inadequate evidence in humans for the carcinogenicity of titanium dioxide.

There is sufficient evidence in experimental animals for the carcinogenicity of titanium dioxide.

Titanium dioxide is possibly carcinogenic to humans (Group 2B).

Rationale: In making this evaluation the Working Group considered the human and animal evidence as well as the evidence regarding potential mechanisms through which titanium dioxide might cause cancer in humans.

The Working Group found little evidence of an increased risk for cancer among humans based on epidemiological data, although relatively few studies were available (IARC, 2010).

The single most informative study was a multi-country study of titanium dioxide production workers that found a slightly increased risk for lung cancer compared with the general population and a suggestive dose–response, but no overall excess risk for kidney cancer. The two other cohort studies reported no increased risks and evidence from the case–control study did not indicate an increased risk for either lung or kidney cancer (IARC, 2010).

Overall, these results led the Working Group to conclude that there was inadequate evidence from epidemiological studies to assess whether titanium dioxide causes cancer in humans (IARC, 2010).

In two studies of rats that inhaled titanium dioxide, one observed an excess incidence of lung tumours in both sexes and another in females only. Studies of rats exposed intratracheally found increases in the incidence of lung tumours. No increases were observed among mice and hamsters exposed intratracheally. Other studies that used different routes of administration did not observe excesses in tumour incidence. On the basis of the results of an increased incidence of lung tumours in rats, the Working Group concluded that there was sufficient evidence that titanium dioxide is carcinogenic in experimental animals (IARC, 2010).

The Working Group considered the body of evidence regarding the pathways and mechanisms by which titanium dioxide or other poorly soluble particles may cause cancer. Following the same line of reasoning as that for the other particles reviewed in this volume, the Working Group considered that the available mechanistic evidence for titanium dioxide was not strong enough to warrant a classification other than Group 2B (IARC, 2010).

Two main pathological processes, atherosclerosis and thrombosis, lead to acute coronary syndromes such as unstable angina and myocardial infarction (Peters, 2006).

Systemic inflammation induced by ambient air pollution is one of the potential mechanisms linking particle deposition in the lung to myocardial infarction. Initial evidence came from an air pollution episode recorded in the mid-1980s when elevated plasma viscosity was observed. Ambient particulate matter has been associated with systemic responses including increases in C-reactive protein (CRP) and fibrinogen in healthy individuals in cross-sectional studies in longitudinal studies, changes in ambient particulate air pollution were associated with changes in the CRP level (Peters, 2006).

There is a strong link between inflammation and coronary heart disease, since factors involved in inflammation and infection seem to play a pro-atherogenic role and inflammation has been identified as a potent risk factor for the acute coronary syndromes (Peters, 2006).

Acute phase proteins, like CRP or fibrinogen, have been identified as biomarkers for inflammatory processes and are important determinants of plaque rupture (Peters, 2006).

Systemic inflammation induced by ambient air pollution is one of the potential mechanisms linking particle deposition in the lung to myocardial infarction. In longitudinal studies, changes in ambient particulate air pollution were associated with changes in the CRP level (Peters, 2006).

The publication of Zeka et al (2006) shows an association between high concentrations of traffic-related particles and increases in inflammatory and thrombotic markers.

Particle number concentrations in ambient air are dominated by the so-called ultrafine particles, particles smaller than 100 nm (Peters, 2006).

An association is observed between particle number concentrations and fibrinogen levels with a lag of 48 hours, and these effects were still evident if particle number concentrations were elevated for at least a week. These data may indicate an acute phase response in association with the high surface area of ultrafine particles and the related oxidative stress exhibited. However, there is also room for the speculation that translocation of ultrafine particles into the blood may be responsible for these observed associations leading to endothelial cell action and subsequent shift to a pro-thrombotic state, here indicated by elevated fibrinogen concentrations (Peters, 2006).

The study is important as it indicates that locally emitted particles with high surface areas and small enough to enter the circulation may be responsible for systemic pro-inflammatory and pro-thrombotic effects. In addition, it suggests that the inflammatory pathways requiring macrophage activation due to fine particle exposures may be only partially responsible for the cardiovascular disease exacerbation observed. Thereby, the data highlight that potentially different particle properties impact on the vascular physiology differently, but the underlying mechanisms are only poorly understood to date (Peters, 2006).

It seems very reasonable that aged aerosol, which is dominated most probably by internally mixed, partially soluble particles, may have more local effects in the lung, while relatively insoluble ultrafine particles with high surface areas may directly interact systemically with vascular functions (Peters, 2006).

 

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