Whereas geometric means of ratios were in a narrow range of 1.1 2.5, the geometric standard deviations and 95th percentiles increased with dose spacing of the involved studies.
This study assessed the occurrence of hormetic dose responses from three previously published data sets [1 3] with 825 chemicals in three Ames assay tester strains (i.e., TA97, TA98, TA100) with and without the S9 fraction, using a five dose protocol and semi-log dose spacing.
Using NOAELs related to lowest LOAELs instead of lowest NOAELs, excluding studies with a dose spacing >8, and standardizing NOAELs to the initial dose animals received shifted the 5th percentile of NOAEL distributions from 0.22 to 0.5 mg/kg body weight per day.
Additionally, the dose spacing in the animal study may have confounded the ratio.
If there is capacity-limited (saturable) absorption of a drug (e.g., lumefantrine), then dose spacing is also a consideration.
The power gains made by the proposed test were even more substantial for 5-fold dose spacing.
We used log2 to reflect the minimal dose spacing, that is, doubling, typically used for in vivo toxicology studies.
As indicated in our simulation study discussed above, this statistic is capable of detecting monotonic nonlinear trends with dose and is not affected by wide dose spacing.
Because of the wide dose spacing and the plateau-shaped response beginning at the low dose of 220 ppm, the NTP trend test was not sensitive enough to detect the dose-related response.
Further, as we observed with the 2-fold dose spacing, in 13 of the 264 patterns (about 5%) the false-positive error rate of the the NTP trend test exceeded the nominal 0.05 significance level and was significantly higher than that of the proposed test.
