English Abstract 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.
