Issues of dosimetry in inhalation toxicity.

A major issue of inhalation toxicity is that of dose. An inhaled dose is more difficult to determine than the dose from other routes of administration. Via oral or parenteral routes, a discrete amount of test substance is given in a bolus. In inhalation toxicology, the delivered dose depends on the exposure concentration and duration, particle size, and associated changes in breathing patterns. Over the past few decades, the concept of dose as applied to toxicological studies has changed considerably. Initially, 'dose' simply meant the concentration in the atmosphere in inhalation studies (or the amount ingested or instilled into the gastrointestinal tract in oral dosing studies) times the duration of study. The extrapolation from one route to another is subject to tremendous errors, and caution is advised when doing so. Default values are, therefore, not recommended and conversion factors must be calculated for each individual situation, making appropriate assumptions about body weight, minute volume, percentage deposition, retention and absorption, also taking into account pulmonary and extrapulmonary pathomechanisms as well as the exposure regimen used in the bioassay and that of actual interest. Also with systemically acting agents caution is advised to perform simple route-to-route extrapolations in the absence of a detailed pharmacokinetic understanding and knowledge of the critical toxophoric moieties.