We estimated the SNCD using the profile likelihood method, by evaluating the SNR at progressively lower doses until the critical SNR was reached (the SNR approaches zero when the dose approaches zero), as illustrated conceptually in Figure 1.
If the SNCD was outside of the experimental dose range for a data set (i.
In addition to calculating the SNCD, we also calculated a point estimate of the extra risk at the SNCD and an upper (one-sided) 95% confidence bound on extra risk at the SNCD ( [UER.
For purposes of comparison of the NOAEL, BMDL, and SNCD as alternative PoDs, it is assumed that the standard UF of 100 is appropriate for establishing an RfD.
This definition implies that the UF applied to the SNCD will depend on the extra risk associated with the SNCD and is thus specific to the data set being analyzed.
The extra risk associated with the NOAEL and the SNCDs becomes lower for data sets that are more informative regarding responses in the low-dose region (median risk for case 4 < median risk for case 3; Table 1); this effect is more pronounced for the SNCD than for the NOAEL.
Comparison of the SNCD with the BMDL and NOAEL The distributions of BMDL: [SNCD.
The SNCD tends to decrease, relative to the other PoDs, for data sets that are more informative regarding responses in the low-dose region (i.
l003327)) and for which an SNCD was derived; all 786 data sets adequate for modeling were included for the NOAEL case.
Establishment of an RfD based on the NOAEL, BMDL, and SNCD.
To compare RfDs based on the SNCD with RfDs based on the NOAEL and [BMDL.
An increased sample size is beneficial for both the SNCD and the BMDL, so that larger experiments will lead to higher human exposure guidelines when using either of these PoDs; a greater benefit was observed for the SNCD-based exposure guideline relative to the BMDL-based exposure guideline (see Supplemental Material, Section 4).