Kalberlah and Schneider approach

In a report on a research project quantification of extrapolation factors (Kalberlah and Schneider 1998), it is noted that extrapolation factors are intended to replace lack of knowledge by a plausible assumption, and that instimtions with responsibihty for establishing the mles must decide which level of statistical certainty, e.g., applicable for 50% or for 90% of a representative selection of substances, is desired for the selection of a standard value. It is furthermore noted that extrapolation factors are required for (1) time extrapolation, e.g., from a subchronic to a chronic duration of exposure (2) extrapolation from the LOAEL to the NAEL (3) interspecies extrapolation, i.e., from experimental animals to humans and (4) intraspecies extrapolation, i.e., from groups of persons with average sensitivity to groups of persons characterized by special sensitivity. In addition to these extrapolations, route-to-route extrapolation, e.g., oral-to-inhalation or dermal-to-oral must also be discussed. 

If no substance-specific knowledge at aU is available for one of the extrapolation steps, the extrapolation factor in each case is used in unaltered form this factor is described as the standard value. 

On average, a factor of 2-3 was considered sufficient for time extrapolation from a subchronic to a chronic duration of exposure. A higher factor is required in order to cover the 90th percentile. 

Extrapolation from the LOAEL to the NAEL using standard factors should not be undertaken the benchmark method should be used instead. 

If physiologically based pharmacokinetic (PBPK) models cannot be used, interspecies extrapolation is best undertaken by means of scaling according to basal metabolic rate, see Section 5.3.2.3. A second aspect, interspecies variability, should be considered in cases where a higher than average level of safety (achieved by consideration of a higher percentile of the substances) is desired. 

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