ABSTRACT
Pulmonary responses to inhaled particles and bers such as crystalline silica or asbestos have long been considered to be major occupational hazards causing chronic respiratory diseases and death among workers in a variety of industries. Examples of these pathogenic particulates include the various forms of asbestos bers, which have been associated with the development of pulmonary brosis (i.e., asbestosis), lung cancer, and mesothelioma. In addition, the causal relationship is well established between exposures to aerosols of crystalline silica particulates and pulmonary inammation, and the consequent development of silica-induced pulmonary brosis (i.e., silicosis) is well established.1-3 Although the toxic effects of silica and asbestos are well established, for most other particulates (with a few exceptions-e.g., coal dust, titanium dioxide, and carbon black), the epidemiological database is rather sparse. As a consequence, rodent inhalation bioassays have become a benchmark for evaluating potential health hazards and estimating human health risks from exposures to airborne particulates. However, increasing numbers of inhalation studies in rats have shown that chronic exposures to high concentrations of insoluble particulates result in the development of pulmonary inammation, brosis, and lung tumors. The application of the concept of inhalation bioassays for estimating these health risks for humans is complicated by interspecies differences in dosimetry and pulmonary responses. One issue that is troublesome stems from the fact that lung tumorigenic effects have been produced in rats by test materials ranging from the biologically active (e.g., silica) to those generally considered to be biologically benign such as titanium dioxide (TiO2) particles. Indeed, with few exceptions most materials of low solubility and low toxicity have produced lung tumors in rats following long-term exposures at high particleoverload concentrations. Alternatively, chronic particle-overload exposures have not produced lung tumors in mice or hamsters.4 Because of the sensitivity in response, the rat inhalation bioassay has been challenged for its appropriateness as a model to extrapolate to humans.5 The scope of this chapter is a focus on interspecies differences in pulmonary responses to inhaled ne particles and nanoparticulates. Rats are frequently used for pulmonary hazard assessments. Although the rat model is sensitive and useful for gauging lung responses to low-solubility particles, the pulmonary effects in rats following chronic (i.e., 2-year) particle-overload exposures inevitably lead to lung tumors for low-solubility particulates. This does not occur in other rodent species such as hamsters or mice. Moreover, the few studies that have been conducted in nonhuman primates or retrospectively in dust-exposed workers show a different pattern of particle deposition, pulmonary responses, and lack of lung tumors. Finally, numerous epidemio logical studies result in carbon black (Cb) and TiO2-exposed workers do not correlate with evidence of lung cancer risk or noncancer respiratory disease. Thus it is concluded that the rat model may be viewed as a sensitive animal model for assessing the lung hazard potency for evaluating low-solubility particulate materials, but is inappropriate for drawing conclusions about lung cancer risk for humans.5 This chapter describes the current database for chronic and subchronic inhalation studies with low-solubility particulates in rats, mice, and hamsters. Subsequently, a section is devoted to the available chronic inhalation studies with dusts comparing rats with nonhuman primates and humans. The interspecies differential lung responses
have also been reviewed in three different subchronic 90-day inhalation studies with pigment-grade, nanoscale TiO2, and Cb studies, wherein rats, mice, and hamsters have been exposed to identical test substances at the same aerosol concentrations. The results of the three subchronic inhalation studies are outlined in this chapter and the general ndings of pulmonary responses of each of the three species are consistent throughout the three study results. The take-home message is that although each of the three species-rat, mouse, and hamster was exposed to aerosols of the same dusts, at the same concentrations, progressive cellular pathological changes in the lungs were documented only in the lungs of exposed rats. These pathological events are initiated by the development of particle overload, followed by sustained inammation and cytotoxicity, and progress to characteristics of broproliferative disease; evidenced by cell proliferative effects, septal brosis, hyperplasia, and eventually development of lung tumors. In Sections 14.4 and 14.5, we focus on the fundamental differences between pulmonary responses in rats to particle overload and the effects observed in primates and humans exposed to high concentrations of dust particles. Indeed, it has also been reported that particle deposition, retention, and pulmonary inammatory patterns are different in the lungs of rats when compared to particle effects investigated in the lungs of both nonhuman primates as well as in the respiratory tracts of heavily exposed workers. It is also noteworthy that detailed and numerous epidemiological studies in workers exposed to TiO2 and Cb particles provide clear evidence of no causal link between particle exposures and lung cancers or other non-neoplastic lung diseases. This chapter focuses on the relevant toxicological database of subchronic and chronic inhalation studies showing the interspecies diffe rences in lung response to particle overload among rodents. Subsequently, the mechanistic differences between pulmonary responses in rats versus humans and nonhuman primates are presented. Accordingly, it is concluded that the rat model presents a uniquely sensitive pulmonary response under conditions of particle overload.
