Methods for Route-To-Route Extrapolation of Dose

Abstract

Results of acute toxicity studies for a variety of chemicals have indicated that, in most cases, although the inhalation route was more effective than the IG route, wide variations in toxicity occurred between these two routes. The major factors that may result in variations in toxicity between routes include: (1) differences in absorption efficiency; (2) differences in systemic effects; (3) occurrence of critical toxicological effects at the portal of entry; (4) first-pass effects resulting in inactivation or activation of the chemical agent before it reaches the target organ; and (5) variations in temporal patterns of target organ concentrations. Extrapolation to determine safe exposure levels during chronic exposure becomes less reliable, not only as information relating to these factors decreases, but also as the quality or length of exposure decreases in the available toxicologic studies. VDC is an example of one of a few chemicals for which both chronic inhalation and oral toxicity data are available, along with detailed pharmacokinetic information. On the basis of the pharmacokinetic data, differences in toxicity between the two routes did not appear to be very likely for this chemical. This conjecture was supported by the results of chronic toxicity studies. Finally, assuming sufficient data and pharmacokinetic parameters are available, this paper presents a useful and practical approach to route extrapolation.