Background

Chronic inhalation of poorly soluble, non-fibrous particles of low toxicity (PSPs) can result in pulmonary inflammation; increase in lung weights, epithelial hyperplasia, fibrosis and eventually in adenomas and carcinomas in the peripheral lung of rats (Lee et al, 1985; Mauderly et al, 1987; Saffiotti et al, 1988; Nikula, 2000; Roller, 2009). This cascade of events runs primarily at exposures to high particle concentrations and thus may be considered a result of the experimental set-up rather than a true reflection of the virtually low intrinsic toxic potential of PSP. The term "high particle concentration” has not been clearly defined but is related to the amount of poorly soluble material deposited daily in the lungs, and thus, the pulmonary clearance rate seems to be a useful indicator to approximate the critical exposure concentration(s) resulting in lung overload conditions. Analysing results from various lung clearance tests in rats and hamsters exposed for several months to a variety of particulate aerosols led to the conclusion that lung clearance is retarded by chronic exposure to respirable particles at concentrations of 3 mg/m3 or higher (Muhle et al, 1988). A similar concept of a so called "critical deposition rate” was based on mathematical analyses of lung clearance rates by Yu et al, 1989 and was defined as "rate above which the overload condition will be present if the exposure time is sufficient”. An alternative definition of "critical deposition rate” may be seen in the threshold dose leading to impaired alveolar macrophage mediated lung clearance, which is equivalent to approximately 1 mg per gram lung tissue (Morrow 1988) or 1 μl per gram of lung (Oberdörster, 1995).

Additionally, it was shown that rats respond more evidently and more intensely to such exposures. Whereas most of the described inflammatory-related pulmonary effects can also be observed in other experimental species, only rats have been shown to respond with lung tumours. Based hereupon, rats are considered to be particularly sensitive towards PSP-induced lung toxicity compared to other rodents, non-human primates as well as humans and that these tumours are rat-specific. Corresponding indications of such species differences following exposures to PSP were shown in comparative studies with different animal species as will be described in more detail hereafter. Consequently, the relevance of the rat as a model for hazard and risk assessments of repeated exposure to PSP for humans is still questioned by a number of critical appraisals. It is now well established that lung effects following chronic inhalation to PSPs of low toxicity occur only at exposures which are concurrently leading to an accumulation of particles in the deep lung as a result of significant impairment of pulmonary particle clearance. This concept of "lung overload” was first introduced by Morrow in 1988 (Morrow, 1988) and the last comprehensive review of available experimental data and a possible rat-specific effect pattern of "lung overload” was developed in the year 2000 by the ILSI Risk Sciences Institute (ILSI 2000).

The main conclusions from this ILSI workshop on `lung overload` can be summarised as follows:

• Hallmark of particle overload is impaired alveolar clearance.
• Precise mechanisms are not known but volumetric inhibition of macrophages and the development of an inflammatory environment seem to be important drivers.
• Differences in potency of various PSPs are obvious and are leading to the need of dosimetric adjustments accounting for differences in deposition and clearance of particles.
• Overload is not a rat specific phenomenon and seems to be generally reversible but may reach conditions where clearance impairment is irreversible.
• Overload contributes to the (species independent) pathogenesis of non-neoplastic lung responses and is a prerequisite for the tumorigenic effects observed in rats. With regard to humans, despite evidence that particle clearance is impaired in many coal workers, no conclusive evidence for increased lung cancer risk exist for workers chronically exposed to coal dust or for workers exposed to other poorly soluble particles.
• For neoplastic lesions, dose-response data from persistent neutrophilic inflammation and cell proliferation can be used as surrogate for risk characterisation

• For non-neoplastic responses, persistent neutrophilic inflammation may also be used as surrogate whereas epithelial cell proliferation is not considered a necessary prerequisite for fibrosis.
• A nonlinear dose-response approach for the characterisation and evaluation of both, neoplastic and non-neoplastic lesions are considered plausible based on the assumed pathogenesis.
• An uncertainty factor of 1 for both neoplastic and non-neoplastic endpoints can be considered sufficient to account for toxicokinetic and toxicodynamic parameters.
• With regard to an appropriate dose metric some estimate/parameter reflecting retained lung burden is recommended together with a full characterisation of the aerosol exposure parameters (e.g. MMAD, particle surface area, density).
• With regard to non-neoplastic responses the rat is considered predictive of a non-neoplastic hazard for humans.
• With regard to neoplastic responses the rat is considered to be more responsive than other species including humans at doses and exposure intervals that result in pulmonary particle overload.
• The mode of action for induced neoplastic responses in rats apparently needs accumulation of particles in lung alveolar and interstitial compartments, persistent inflammation and epithelial cell proliferation.

In the context of the present review the validity of the above conclusions with regard to the observed lung effects of respirable poorly soluble particles of low toxicity are re-assessed based on recent research findings.