Particle Overload in Toxicological Studies: Friend or Foe?

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 hum...