Particle Overload in Toxicological Studies: Friend or Foe?

Abstract

ABSTRACT

The overloading of particle clearance is an important issue in the design and interpretation of inhalation toxicological studies. This issue is particularly important in chronic inhalation bioassays in rats, in which overloading is associated with inflammation, epithelial proliferation, and fibrosis, which may amplify carcinogenic responses or, as suggested by some, even induce cancer regardless of the inhaled material. At present, the key issue is whether or not data from exposures causing overload in animals are useful for predicting health effects in man. A review of reports of chronic inhalation studies in rats exposed to a spectrum of materials suggests that not all exposures resulting in overloading cause cancer, and that the cancer incidences from exposures causing overloading appear to reflect the relative carcinogenic potentials of the test materials. Data from such exposures, however, do little to establish the exposure-response relationship at lower doses most typically relevant to human exposures. Responses observed under overload conditions may be relevant to responses of humans exposed to high (occupational) levels of dusts, of humans with clearance impairments, or of humans in whom inflammation, epithelial proliferation, or fibrosis are concurrently induced by other agents. We need to know more about the relative contributions of carrier particles and particle-borne carcinogens to carcinogenicity under overloaded and non-overloaded conditions. We need to know more about the function of retained particles as reservoirs of particle-borne carcinogens. We need to know more about the potential amplification of carcinogenic responses at low doses by clearance impairments and inflammatory, proliferative, and fibrotic responses induced by other agents. Most importantly, we need a better understanding of the mechanisms of carcinogenesis. At this time, we have sufficient ability to design animal studies to either include or avoid overload. It is concluded that it may be useful to include at least a "minimal overload" level in inhalation bioassays of poorly-soluble particles, and that this approach might be a useful substitute for the classical maximum tolerated dose in setting exposure limits.