Concentration * Time = constant? The validity of Haber's Law in the extrapolation of discontinuous to continuous exposition

Abstract

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In general, the exposure of experimental animals to inhalable compounds is discontinuous rather than continuous. Of interest however are the chronic toxic effects which occur after a lifetime of continuous exposure. For the extrapolation of discontinuous to continuous exposition Haber's Law: Concentration * Time = constant (toxic) effect is applied. In this report, the underlying assumptions of Haber's rule are reviewed. From studies of literature, it is concluded that Haber's Law has limited validity. It can be reasoned that only at low dose ranges at which toxicokinetic processes are far from saturated, Haber's Law may be valid. Unfortunately, no scientific data are available on the validity of Haber's Law in the NOAEL-dose range. Therefore, no clear statements on the validity of Haber's Law in the extrapolation of NOAELs of discontinuous to continuous exposure can be made. However, it can be reasonably expected that Haber's rule may be valid for certain groups of compounds. These compounds include: 1. agents with direct local irreversible toxicity. 2. agents with direct systemic irreversible toxicity which equilibrate rapidly with the blood. 3. agents with indirect irreversible toxicity of which the toxic metabolites hardly undergo further detoxification and evoke a rapid toxic response. In case of systemic toxicity a rapid equilibration with the blood is a prerequisite.