Pulmonary carcinogenicity of inhaled particles and the maximum tolerated dose.

Chronic inhalation bioassays in rodents are used to assess pulmonary carcinogenicity for purposes of hazard identification and potentially for risk characterization. The influence of high experimental doses on tumor development has been recognized for some time and has led to the concept of maximum tolerated dose (MTD) for dose selection, with the highest dose being at the MTD. Exposure at the MTD should ensure that the animals are sufficiently challenged while at the same time the animal's normal longevity is not altered from effects other than carcinogenicity. A characteristic of exposure-dose-response relationships for chronically inhaled particles is that lung tumors are significantly increased only at high exposure levels, and that lung tumors are seen in rats only but not in mice or hamsters. This lung tumor response in rats is thought to be secondary to persistent alveolar inflammation, indicating that the MTD may have been exceeded. Thus, mechanisms of toxicity and carcinogenicity may be dose dependent and may not operate at lower doses that humans normally experience. Despite awareness of this problem, carcinogenicity bioassays that evaluate particulate compounds in rodents have not always been designed with the MTD concept in mind. This is due to several problems associated with determining an appropriate MTD for particle inhalation studies. One requirement for the MTD is that some toxicity should be observed. However, it is difficult to define what degree of toxic response is indicative of the MTD. For particle inhalation studies, various noncancer end points in addition to mortality and body weight gain have been considered as indicators of the MTD, i.e., pulmonary inflammation, increased epithelial cell proliferation, increased lung weight, impairment of particle clearance function, and significant histopathological findings at the end of a subchronic study. However, there is no general agreement about quantification of these end points to define the MTD. To determine whether pulmonary responses are indicative of the MTD, we suggest defining an MTD based on results of a multidose subchronic and chronic inhalation study with a known human particulate carcinogen, e.g., asbestos or crystalline silica. Quantification of effects in such a study using the noncancer end points listed above would identify a dose level without significant signs of toxicity at the end of the subchronic study. If this dose level still results in significant lung tumor incidence at the end of the chronic study. We will have a sound basis for characterizing the MTD and justifying its use in future particle inhalation studies. Also, a better understanding of cellular and molecular mechanisms of particle-induced lung tumors is needed to support the MTD concept.