Dose-Response Curve LOAEL-to-NOAEL Extrapolation

7 DOSE-RESPONSE CURVE (LOAEL-TO-NOAEL EXTRAPOLATION) 

One of the most evident limitations in the NOAEL approach in the derivation of tolerable intakes is that it does not take into account the slope of the dose-response curve for the particular response of interest (Section 4.2.4). The NOAEL is by definition one of the doses tested, and apart from ensuring that the number and spacing of data points are adequate to provide a reasonable estimate of the NOAEL, all other data points are ignored. Although the NOAEL could be considered an estimate of the tme NAEL, the quality of the estimate cannot be assessed. For the dose-response relationship and precision in the NOAEL, consideration should therefore be given to the uncertainties in the NOAEL as the surrogate for the NAEL. 

In case a NOAEL cannot be set for the critical effect, a LOAEL is then set and extrapolated to a NOAEL. The extrapolation from a LOAEL to a NOAEL can be regarded as part of the dose-response analysis. Consideration should therefore also be given to the uncertainties in the extrapolation of the LOAEL to the NAEL in cases where only a LOAEL is available as the starting point for the assessment. 

Assessment factors between 1 and 10 have been suggested or applied by various national and international bodies for the extrapolation from a LOAEL to a NOAEL. Some analyses have been performed in order to evaluate the magnitude of an appropriate assessment factor for the LOAEL-to-NOAEL extrapolation, based on evaluations of LOAEL/NOAEL ratios. This section gives an overview of such analyses and evaluations. Then, the key issues are summarized and our recommendations are presented. 

Dourson and Stara (1983) made a plot of frequency versus ratios of LOAEL to NOAEL for either subchronic (27 comparisons) or chronic exposure (25 comparisons), or their combination (52 comparisons) based on data adapted from Weil and McCollister, see Section 5.6. They stated that these experimentally determined ratios can be thought of as reductions in a LOAEL found after subchronic or chronic exposure in order to yield the corresponding NOAEL. For example, a ratio of 3 indicates that the NOAEL is threefold less than the corresponding LOAEL for a particular chemical. All chemicals had ratios of 10 or less and of these ratios, 96% had values of 5 or less. The authors concluded that this analysis supported a UF between 1 and 10 to account for estimating an ADI from a LOAEL if a NOAEL is not available. 

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

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