Dosimetric comparisons of particle deposition and retention in rats and humans

Much of the information on the toxicity of particulate matter (PM) comes from studies in which laboratory rats were exposed to PM by inhalation or instillation. Optimal use of these toxicologic data requires extrapolation to the human scenario. Assuming that comparable doses should cause comparable effects across species and that species respond similarly to a given dose at a target site, extrapolations only require that dose be defined and then characterized. Dose may be defined in terms of a PM indicator (e.g., particle number or mass), a respiratory region, and the time over which the dose is integrated (i.e., deposited versus retained dose and incremental versus accumulated dose). Dose must also be normalized: for example, unit of dose per body mass, respiratory region surface area, or number of alveolar macrophages. The parameters chosen to define a normalized dose can drastically affect the rat exposure concentration required to provide a normalized dose equivalent to that occurring in a human. The publicly available multiple path particle dosimetry model developed by CIIT Centers for Health Research was used to predict particle deposition and retention in rats and humans. Estimates of particle concentration and exposure duration required for a rat to receive the same dose as received by a human were obtained with consideration of daily activity levels and ambient PM size distributions. These techniques were also used to compare dose and response between rats and humans in several published studies. Results indicate that the relationship between PM dose and response may differ between rats and humans. For acute PM exposures, rats may be less susceptible to inflammatory responses than humans. For chronic exposures to high levels of PM, however, an overload of alveolar clearance in rats may cause them to become more susceptible than humans to adverse pulmonary effects. The dosimetric calculations indicate that to achieve nominally similar acute doses per surface area in rats, relative to humans undergoing moderate to high exertion, PM exposure concentrations for rats would need to be somewhat higher than for humans. Since the clearance of PM is faster from the lung of rats than humans, much higher exposure concentrations are required for the rat to simulate retained burdens. In other cases, rats will require lower exposures than humans to have comparable doses, illustrating the complexity of such analyses. To make accurate estimates of dose, it is essential to have accurate and complete information regarding exposure conditions-that is, not only concentration and duration of exposure, but also the aerosol size distribution. Establishing a firm linkage between exposure and dose requires that consideration be given to particle characteristics, definitions of dose metrics, and biological normalizing factors.