Human risk assessment of dermal and inhalation exposures to chemicals assessed by route-to-route extrapolation: the necessity of kinetic data.

In toxicity testing the oral route is in general the first choice. Often, appropriate inhalation and dermal toxicity data are absent. Risk assessment for these latter routes usually has to rely on route-to-route extrapolation starting from oral toxicity data. Although it is generally recognized that the uncertainties involved are (too) large, route-to-route extrapolation is applied in many cases because of a strong need of an assessment of risks linked to a given exposure scenario. For an adequate route-to-route extrapolation the availability of at least some basic toxicokinetic data is a pre-requisite. These toxicokinetic data include all phases of kinetics, from absorption (both absorbed fraction and absorption rate for both the starting route and route of interest) via distribution and biotransformation to excretion. However, in practice only differences in absorption between the different routes are accounted for. The present paper demonstrates the necessity of route-specific absorption data by showing the impact of its absence on the uncertainty of the human health risk assessment using route-to-route extrapolation. Quantification of the absorption (by in vivo, in vitro or in silico methods), particularly for the starting route, is considered essential.