Biomathematical models of exposure-dose-response to respirable quartz in Fischer 344 rats, Cynomolgus monkeys, and humans.
Toxicologist 2003 Mar; 72(S-1):44
A biomathematical model was developed to describe clearance and retention kinetics of respirable quartz and pulmonary responses, including the recruitment of alveolar macrophages (AMs) and polymorphonuclear leukocytes (PMNs) and the production of superoxide dismutase (SOD) in bronchoalveolar lavage (BAL) fluid, as well as hydroxyproline (HP) in lung tissue. The model was first calibrated in Fischer-344 rats exposed to respirable crystalline silica (15 mg/m3 for up to 6 months) and validated using data from two additional rat studies (respirable quartz exposures 0.74 mg/m3 for 2 years, and 10 mg/m3 for 75 days). The model was then extrapolated to Cynomolgus monkeys and humans by adjusting model parameters for species differences such as breathing rates, lung mass, and surface area. To evaluate model fit, BAL data and limited quartz lung burden data were available in Cynomolgus (10 mg/m3 quartz for up to 26 months) and in coal miners "0.1 mg/m3 mean quartz in respirable coal mine dust for 17 years). The model predicted well the end of study lung burden in monkeys and the lavageable quartz mass in two humans; however, it overpredicted the pulmonary cell responses by several fold. This was consistent with the observed dose-response, in which the rat PMN and AM counts were several times greater than those in monkeys at higher doses (cell counts relative to controls and normalized to lung surface area). Human predicted dose-response data were in the low dose region, where responses were similar across species, except for two individuals, whose PMN counts exceeded those expected from the rat data. The relative increases in SOD and HP were comparable across species. Despite some differences in magnitude, similar patterns of nonlinear dose-response were observed in all three species. These biomathematical models may be useful in risk assessment by providing a mechanistic basis for extrapolating rat responses to various inhaled particulates in humans.
Models; Mathematical-models; Respirable-dust; Quartz-dust; Silica-dusts; Man-made-mineral-fibers; Pulmonary-system-disorders; Laboratory-animals; Coal-mining; Respiratory-system-disorders
Research Tools and Approaches: Risk Assessment Methods
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah