Dose-Response Curve LOAEL-to-NOAEL Extrapolation and

1 Dose-Response Curve (LOAEL-to-NOAEL Extrapolation) Summary AND Recommendations 

The NOAEL is not very accurate with respect to the degree to which it corresponds with the (unknown) tme NAEL. One of the most evident limitations in the NOAEL setting is that it does not take into account the shape of the dose-response curve, including its slope, for the effect as the NOAEL by definition is one of the doses tested in the specific experimental study, and all other data points are ignored. In case a NOAEL cannot be set for the critical effect, a LOAEL is then set and extrapolated to a NOAEL this extrapolation can also be regarded as part of the dose-response analysis. 

If sufficient data are available, the shape of the dose-response curve should be taken into account. In the case of a steep curve the derived NOAEL can be considered as more reliable (the greater the slope, the greater the reduction in response to reduced doses) in the case of a shallow curve, the uncertainty in the derived NOAEL may be higher and this has to be taken into account in the assessment. If a LOAEL has to be used in the assessment, then this value can only be considered reliable in the case of a very steep curve. 

In theory, the steeper the slope of the dose-response curve, the smaller the assessment factor and vice versa. However, there is no scientific basis for any value of a default factor to account for uncertainty in the NOAEL, nor any distribution. 

A default assessment factor of 10 has been used traditionally for the extrapolation from a LOAEL to a NOAEL. Some analyses have been performed in order to evaluate the size of an appropriate assessment factor for the LOAEL-to-NOAEL extrapolation, based on evaluations of LOAEL/NOAEL ratios. A number of evaluations have been based on data from Weil and McCollister (1963) and adapted by Dourson and Stara (1983). Some evaluations found that this analysis supports that a factor of 10 or lower is adequate while others found the factor of 10 to be overly conservative as the LOAEL rarely exceeded the NOAEL by more than about 5-6 fold and was typically closer to a value of 3. The analysis on LOAEL/NOAEL ratios performed on LOAEL/NOAEL ratios showed 95th percentiles of 9, 16, and 11 for subacute, subchronic, and chronic exposure durations, respectively, supporting the 10-fold factor to account for about 95% of the chemicals evaluated. 

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