Pharmacokinetic modeling approaches for describing the uptake, systemic distribution, and disposition of inhaled chemicals

A fundamental relationship in toxicology is that an external chemical exposure leading to an internal tissue dose can result in an adverse biological response. An understanding of these relationships in experimental animals is often used to extrapolate and predict the potential risk to humans following exposure to toxic chemicals. The exposure-dose-response relationships for volatile compounds inhaled by the lungs are complicated by the fact that many toxic effects caused by these chemicals have been identified in tissues and organ systems other than the lungs. Pharmacokinetic modeling approaches have been devised to quantitate the relationships between inhaled concentrations of volatile compounds and the resulting critical tissue doses in experimental animals. These animal models have also been extrapolated to predict chemical disposition in humans for estimation of human health risks. This communication reviews three pharmacokinetic descriptions, each representing different levels of complexity, that have been used to assess chemical disposition of inhaled, volatile chemicals. The mathematical structures, assumptions, data needs, and risk assessment capabilities of each modeling approach are described.