Uptake Kinetics,Species Differences,and the Determination of Equivalent Combinations of Air Concentration and Exposure Duration for Assessment of Acute Inhalation Toxicity

For acute inhalation toxicity assessment, I develop a conceptual framework for expressing combinations of intensity (air concentration) and duration that produce equivalent toxicity by examining how the shape of the body-burden uptake curve during a bout of inhalation interacts with various pharmacodynamic measures of the critical body burden needed to produce toxicity. If toxicity depends on attaining a critical tissue concentration, three existing empirical approaches—Haber's Law, the ten Berge equation, and pure air-concentration-dependence—are but local approximations to different parts of an overarching mathematical relationship. The compound-specific half-life of elimination determines the range of durations for which each applies: durations of one half-life or shorter follow Haber's Law, exposures of 4 or more half-lives follow pure air-concentration-dependence, and intermediate durations can be approximated by the ten Berge equation. Better animal-to-human extrapolation is achieved if exposure durations are expressed as number of species-specific half-lives. I consider several alternative pharmacodynamic criteria, such as the dependence of toxicity on time spent above a critical tissue concentration, or on the area under the tissue concentration curve, on the tissue concentration of a toxic metabolite, or on the imbalance of damage and repair processes.