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Statement of Overall Conclusions

The rat is uniquely sensitive to the formation of lung tumours when exposed under conditions of particle overload to titanium dioxide and other poorly soluble low-toxicity particles (Levy, 1995). Although particle overload is observed in other experimental species, such as the mouse, it is only in the rat that a sequence of events is initiated that leads to fibroproliferative disease, septal fibrosis, hyperplasia and eventually lung tumours. Similar pathological changes are not observed in other common laboratory rodents, in non-human primates, or in exposed humans. In addition, detailed epidemiological investigations have shown no causative link between titanium dioxide exposure and cancer risk in humans. At workplace exposure concentrations, no lung cancer hazard has been observed. Thus, a carcinogen rating for titanium dioxide is not warranted.

 

Epidemiological studies on occupationally exposed workers

 

Cohort studies

Chen and Fayerweather (1988) examined mortality and cancer incidence in a cohort of 1576 male workers exposed to titanium dioxide for more than a year in two titanium dioxide production plants in the United States. Mortality due to cancer was significantly lower than expected on the basis of national rates, and mortality due to lung cancer (9 deaths) was also significantly reduced (SMR=0.52; 95% CI 0.24-0.99). Nested case-control analyses found no significant associations between titanium dioxide exposure and risk of lung cancer, chronic respiratory disease, or chest roentgenogram abnormalities. In addition, a subsequent nested case control study restricted to the oldest and largest of the two plants, was able to adjust for cigarette smoking habits, and also reported no increased risk with estimated exposure to titanium dioxide (Fayerweather et al., 1992).

The study by Ellis et al. (Ellis et al, 2010: Ellis et al, 2013) is an update and extension of the Chen and Fayerweather (1988) study which included workers from two titanium dioxide processing plants. The plants are not described by Chen and Fayerweather (1988), but Fayerweather et al (1992) notes that one is a large plant on the US east coast (Edgemoor) where all the cancer deaths in the study occurred, and the other is a smaller west coast plant. The study by Ellis et al (2010) included workers from the Edgemoor plant (the data from Chen and Fayerweather 1998 which included workers employed through 1983, were used as the basis for this study with worker data updated from 1983 onward) and two other plants (New Johnsonville and De Lisle). None of the workers were included in the US multicentre study by Fryzek et al (2003). Ellis et al (2010) included over 5000 production workers and 133 lung cancer deaths of which 111 occurred among Edgemoor workers (Chen and Fayerweather et al 1988 reported 9 lung cancer deaths among Edgemoor workers). Lung cancer mortality was less than expected (SMR = 0.90; 95% CI, 0.75-1.05), and no exposure-response relationship was found between TiO2 and mortality from lung cancer and non-malignant respiratory disease.

 

Fryzek et al. (2003) conducted a retrospective cohort mortality study of 4241 workers (3,832 males) employed for more than 6 months at 4 production facilities in the US. Mortality from all cancers was lower than expected (SMR=0.8; 95% CI 0.7-1.0) but the number of lung cancer deaths (61) was close to expected (SMR = 1.0; 95% CI 0.8–1.3). Workers with the highest titanium dioxide exposure (packing, micronizing or internal recycle workers) had a similar mortality pattern, i.e., lower than expected deaths for all cancer with no excess for lung cancers. Internal analyses showed that relative risks of all cause mortality and mortality due to lung cancer and non-malignant respiratory disease fell with increasing cumulative exposure. The investigators concluded that the data indicate that workers at the US plants have not experienced increased risks of lung cancer or other significant adverse health effects as a result of their occupational exposures to titanium dioxide.

 

The largest cohort study (Boffetta et al., 2004) included 15,017 titanium dioxide workers (14,331 males) employed for more than a year in 11 plants in six European countries (Finland, France, Germany, Italy, Norway, and the United Kingdom). Deaths due to all malignant neoplasms were fewer than expected (SMR = 0.98; 95% CI 0.91–1.05), but deaths due to lung cancer (306) were significantly higher than expected on the basis of national rates (SMR = 1.23; 95% CI 1.10–1.38). However, it was noted that lung cancer mortality rates were higher than corresponding national rates in eight out of ten locations where factories are located, i.e. the SMRs would have been lower if the investigators had used regional reference rates. Hext et al. (2005) noted that regional lung cancer mortality rates were approximately one fifth higher on average for workers in the study than national rates. Boffetta et al. (2004) undertook a very detailed and reliable exposure assessment for titanium dioxide and potential occupational confounders but internal analyses showed no evidence of an exposure– response relationship between estimated exposure to titanium dioxide dust and lung cancer mortality. The investigators concluded that the results of the internal analyses point towards the lack of a carcinogenic effect on the lung of titanium dioxide dust exposure, as experienced in this industry.

 

Case-control studies

Siemiatycki (1991) conducted a hypothesis-generating case-control study in Montreal that included male patients with 20 different types of cancer and assessed exposure to 293 substances including titanium dioxide. A more refined analysis of the relationship between titanium dioxide and lung cancer in the Montreal study was later performed by Boffetta et al. (2001) and which incorporated an improved exposure assessment, which resulted in several changes to the ascribed exposure status of subjects. Boffetta et al. (2001) included all 857 cases of lung cancer of the original study, but constructed a new group of 1066 controls comprising all 533 population controls and a random sample of 533 of the 1349 cancer controls (subjects with cancers of other organs) included by Siemiatycki (1991). Odds ratios (OR) were adjusted for confounders including smoking history and were not elevated for ever exposure to titanium dioxide (OR=0.9; 95% CI 0.5-1.5; 33 cases) or substantial exposure (OR=1.0; 95% CI 0.3-2.7; 8 cases).

Ramanakumar et al. (2008) has reported on combined results from the case-control study conducted by Siemiatycki (1991) and another large population case control study conducted in Montreal (Ramanakumar et al., 2006) which included 1236 cases of lung cancer (765 males) and 1512 population controls (899 males). OR adjusted for a number of possible confounders including smoking, were calculated using population and cancer controls in the former study, for male and female subjects in the latter study, and for the combined group of 2093 lung cancer cases and 3394 controls. In both studies there was no evidence of excess risk among subjects who had been exposed to titanium dioxide and also in pooled analyses, OR were close to unity for any exposure to titanium dioxide (OR=1.0; 95% CI 0.6-1.7; 76 cases) and substantial exposure (OR=1.2; 95% CI 0.4-3.6; 8 cases). The authors concluded that occupational exposure to titanium dioxide did not produce an excess risk of cancer, consistent with the evaluations of the IARC working group.

Conclusion

The epidemiological studies are well conducted, and the findings are robust and replicated in all three large cohort studies and two large case-control series. Statistical power is not a limitation of the epidemiological studies as the three key cohort studies (Fryzek et al, 2003; Boffetta et al, 2004; Ellis et al, 2010) include over 24,000 production workers in 18 manufacturing plants in 7 countries, with a total of 457 expected lung cancer deaths of which a high proportion were expected after a sufficient latency period. The Canadian case-control studies included 2093 lung cancer cases (Boffetta et al, 2001; Ramanakumar et al, 2008).

In summary, no causative link between titanium dioxide exposure and cancer risk in humans has been demonstrated.