Duration of Exposure Extrapolation Summary and

The most relevant study to base a hazard assessment and derivation of a tolerable intake upon is a study that reflects the human exposure situation as well as possible. Eor numerous substances, data are only available from acute (single exposure), subacute (14—28 days), or subchronic (90 days) animal studies. In order to derive, e.g., a TDl or RfD for such a substance, it may be necessary to base the assessment on data from a shorter duration study. An assessment factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that, in general, the experimental NOAEL will decrease with increasing exposure duration as well as other and more serious adverse effects may appear with increasing exposure duration. 

Also bioaccumulating substances may in some situations call for a higher assessment factor. If accumulation is likely, the toxicity studies need to be of sufficient length to cover the accumulation period (e.g., the time to reach a steady-state concentration). If there is limited information on these aspects, it has to be considered to which extent this lack of information should affect the assessment factor. 

A lower assessment factor may be applied if there is evidence that the exposure duration is of no or low importance. If it is assumed that the effect is concentration-dependent rather than dose-dependent, which might be the case for certain local effects, no assessment factor for duration of exposure may be considered necessary. 

A default factor of 10 has been applied by some national and international bodies. A number of analyses for an appropriate assessment factor have been based on evaluations of the ratios of NOAELs and LOAELs for studies of different duration performed in various animal species exposed orally or by inhalation. The most extensive analyses are those performed by Kalberlah and Schneider (1998) and Vermeire et al. (1999, 2001). 

WHO/IPCS (1994, 1996, 1999) did not consider an extrapolation factor for duration of exposure specifically, but the uncertainty related to this element is included in a broader defined additional factor addressing the adequacy of the overall database (Section 5.9). The US-EPA (1993) has adopted the 10-fold factor to account for the uncertainty involved in extrapolating from less than chronic NOAELs to chronic NOAELs. This default value has later on been reconfirmed (US-EPA 2002) when only a subchronic duration smdy is available to develop a chronic reference value no chronic reference value is derived if neither a subchronic nor a chronic smdy is available. For systemic effects, ECETOC (2001) recommended a default assessment factor of 6 for extrapolation from subacute (28 days) to chronic exposure, and a factor of 2 from subchronic (90 days) to chronic exposure. For local effects, no additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity. KEMl (2003) suggested that extrapolation from subchronic to chronic exposure should be based on the distribution of NOAEL ratios reported by Vermeire et al. (2001) with an assessment factor of 16 covering 95% of the substances compared and for extrapolation from subacute to chronic exposure, with an assessment factor of 39 covering 95% of the substances. 

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