Technical Report 122

(AOP) rat

The development of pulmonary tumours in rats after PSP exposures occurs only under the conditions of sustained particle overload in the lungs. This pulmonary pathological response in rats is unique, as other rodent species (i.e., mice/hamsters) and larger mammals such as humans or non-human primates do not develop lung tumours under similar conditions of particle lung overload. The evidence to support this conclusion has been addressed in some of the studies listed above: 1) chronic particle overload PSP exposures produces lung tumours in rats, but not in mice; 2) in subchronic inhalation studies with ultrafine TiO2 and carbon black particles rats, mice and hamsters have been exposed to identical test substances at the same concentrations. Rats, but not mice or hamsters developed atemporal pathological sequelae in lung responses to particle overload conditions. This is initiated by sustained lung inflammation and cytotoxicity responses, followed sequentially by accelerated cell proliferative and fibroproliferative effects (e.g., hyperplasia, septal fibrosis, secondary genotoxicity, etc.); ultimately leading to lung tumour development. Contributing to this pathological scenario conceivably could be the generation "abnormally high” pro-inflammatory responses, concomitant with a deficiency in anti-inflammatory cytokine responses, leading to a perpetual imbalance of adverse effects in the rat lung. This would appear to be a potentially important mechanism for either increasing the sensitivity and/or overriding the protective capacity of the rat lung response to particle overload. Table 2 summarises the difference in the pulmonary responses to particle overload exposures in rats vs. mice, hamsters and primates/humans.