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2009
Conference Paper
Titel
Evaluation of risk assessment factors for inter-species and time-extrapolation
Titel Supplements
Abstract
Abstract
For human risk assessments extrapolation of experimental data to the real human exposure situation is required. In this context the REACH guidance document has proposed default extrapolation factors for inter-species differences, as well as for differences in duration of exposure. Already several groups have analysed interspecies and time-extrapolation factors, but predominately based on limited datasets (Kalberlah et al., 2002; Vermeire et al., 2001; Pieters et al., 1998). The Fraunhofer Institute ITEM has developed the database RepDose on subacute to chronic toxicity studies in rodents. The high quality and amount of data in RepDose allows to reevaluate the current extrapolation factors for rats and mice and for time-extrapolation. A tiered approach is applied to evaluate both assessment factors distinguishing oral and inhalation exposure. Based on allometric considerations, for toxicokinetic properties a factor of 7 is proposed by the guidance to extrapolate doses as mg/kg bw from mice to humans and a factor of 4 for rats. Thus an extrapolation factor of 1.75 would account for differences between rats and mice. Further according to the guidance a factor of 2.5 is applied to account for toxicodynamic differences between species. The data in RepDose show, that on average the differences between both species are smaller than the standard extrapolation factor. Assessment factors for time-extrapolation are derived for subchronic to chronic, subacute to chronic and subacute to subchronic exposure. For the chemicals covered in RepDose, in general lower time-extrapolation factors are derived compared to those proposed by the REACH guidance document. The impact of local effects and certain physical-chemical properties like accumulation is described.