SPECIES DIFFERENCES AND MECHANISMS OF LUNG TUMOuR FORMATION IN RATS

In experimental toxicity studies, the rat model is known to be particularly sensitive to the development of lung pathological responses under conditions of particle overload. Lung tumours have been reported only in rats, but not mice or hamsters, exposed to low toxicity, low solubility particulates following chronic exposures to high particle concentrations. This disparity in lung responses among the rodent species has clearly been demonstrated following 90-day and chronic (two year) inhalation studies in rats, mice and hamsters to similar test substances and identical concentrations of the same test substances including pigment-grade and ultrafine titanium dioxide (TiO2) particles and carbon black particulates. It is interesting to note that although particle overload was documented in the mouse lung, it was only in the rat that a sequence of pulmonary pathogenic events was initiated which progressed to fibro-proliferative disease, evidence by septal fibrosis, hyperplasia and eventually lung tumours. The results of experimental studies clearly demonstrate that under virtually similar or identical exposure conditions, pathological changes are documented in rats, but are not observed in other rodent species (mice or hamsters). Furthermore, it has also been well demonstrated that particle deposition, retention and inflammatory patterns are different in the lungs of rats when compared to particle effects investigated in the lungs of non-human primates. It is also noteworthy that detailed epidemiological studies in TiO2 and carbon black workers provide unequivocal evidence of no causal link between particle exposures and lung cancers or other non-neoplastic lung diseases. This Section details the relevant toxicological database demonstrating the interspecies differences in lung response to particle overload, thus clearly demonstrating that the rat model presents a particularly sensitive pulmonary and, moreover, a unique lung neoplastic response under conditions of particle overload.