Relevance of cell proliferation

Repeated inhalation exposure to particulates, whether inherently acutely toxic or not, represent one of the key drivers for the development of toxicological relevant proliferative lesions in the respiratory tract. Cellular damage resulting from repeated exposure to toxicants, induces patho-physiological repair processes during which damaged tissue may proliferate (hyperplasia) and/or undergo metaplasia to a different, more resistant cell type (e.g. fibrosis) if return to normal cell morphology is not complete. The site of these changes is heavily dependent upon the nature of the toxicant and the type of tissue exposed. In case of particulate matter, physical-chemical properties such as particle size (Section 2) and (bio)solubility (Section 3) are also of importance. Ciliated columnar and olfactory epithelia are the most fragile respiratory epithelia and thus the most susceptible to damage from inhaled toxicants. Cuboidal epithelium is more resistant, and squamous epithelium is the most resistant to damage from direct contact with toxic or irritant materials (Renne et al, 2009).

Increased epithelial cell proliferation and lung tumour formation following long-term exposure of rats to different PSPs have been reported (Miller and Hook 1990, Muhle et al 1990, Heinrich et al 1995, Nikula et al 1997, Mauderly 1997).

Repeated inhalation exposure of rodents to cytotoxic or irritant materials, may result in degeneration and necrosis of epithelial surfaces, inflammation, interstitial fibrosis, metaplasia and hyperplasia of damaged bronchiolar and alveolar epithelium. Whereas bronchiolisation occurs rarely spontaneously in rats, it is frequently observed in centriacinar regions of the lungs of rats following chronic inflammation due to repeated exposures (Brix et al, 2004). However, three types of alveolar-bronchiolar hyperplasia (an alveolar type, a bronchiolar type and a mixed type) as potential preneoplastic lesions have been observed in the rat lung following repeated exposures to relatively inert particulates (Mohr et al, 1990; Muhle et al, 1995). In rats, continued severe epithelial hyperplasia and metaplasia may then progress to malignant epithelial neoplasia. However, in contrast to rats, bronchiolisation was not observed in mice or hamsters exposed to comparable concentrations of TiO2 (Bermudez et al, 2002) or carbon black (Elder et al, 2005).

In conclusion, a synopsis of available data suggest that the ability of particles to induce persistent lung inflammation is key in the initiation of cell proliferation and tissue remodelling as necessary prerequisites for non-neoplastic lung lesions (e.g. fibrosis) as well as the fixation of secondary caused mutations in affected target cells and, in the rat, the progression of these cells also to neoplastic lesions. Hence it follows, that the induction of cell proliferation and all subsequent events resulting hereof are threshold related.