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Supplemental Material is available online (http://dx.doi.org/10.1289/EHP408).
This research was conducted in part while S.S. was a Visiting Scientist at the McLaughlin Centre for Population Health Risk Assessment at the University of Ottawa in 2014 and 2015. The work of F.P. and R.R.T. was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. D.K. is employed by the University of Ottawa and by Risk Sciences International, Ottawa, Canada.
Received: 21 January 2016; Revised: 25 April 2016; Accepted: 13 June 2016; Published: 6 July 2016.
Caption: Figure 1. Illustration of the three types of point-of-departure (POD) approaches considered in the study. Nuclear receptor assay concentration response data on pimozide is used as an example (solid circles). The Hill model has been fitted to the data: in all three cases, the solid curves that describe the mean response are the same, but the two-sided 90% confidence intervals around the mean response (the dotted curves) depend on the POD approach considered. (4) The benchmark dose (BMD) associated with a 10% extra effect ([BMD.sub.10e]) is 0.24 units (solid red vertical line), and the lower 5th and upper 95th confidence limits (vertical dotted lines) are 0.15 ([BMDL.sub.10e]) and 0.37 units, respectively. (B) The BMD associated with a 10% additional effect ([BMD.sub.10a]) is 0.28 units (solid red vertical line), and the lower 5th and upper 95th confidence limits (vertical dotted lines) are 0.18 ([BMDL.sub.10a]) and 0.42 units, respectively. (C) The [SNCD.sub.1.0] associated with a signal-to-noise ratio (SNR) of 1.0 is 0.31 units (solid red vertical line). The difference between the lower and upper bounds on absolute effect at the SNCD is [equivalent] 10.4 - (-1.2) = 11.6 (difference between the horizontal dotted lines). Because the SNR is 1.0, this approximates to the point estimate of additional effect at the signal-to-noise crossover dose (SNCD), which is [equivalent] 4.6 - (-7.0) = 11.6 (difference between the horizontal solid line and the background response according to the fitted model). In this example, [SNCD.sub.1.0] is approximately twice the size of the BMDLs.
Caption: Figure 2. Ratios of the [BMDL.sub.e] to the SNCD with BMDLs defined in terms of extra effects of 5%, 10%, 20%, 30%, and 40%. Ratios are given in terms of medians (solid circles) and intervals describing the lower 5th and upper 95th percentiles, based on different stratifications of the data. Red (large) circles correspond to results based on all selected curves (n = 8,456); blue circles correspond to results based on cytotoxicity assays (n = 3,130); yellow circles correspond to results based on nuclear receptor assays (n = 4,603); and cyan circles are results based on stress response assays (n = 723). (4) Ratios of the [BMDL.sub.e] to the [SNCD.sub.1.0]. (B) Ratios of the [BMDL.sub.e] to the [SNCD.sub.0.67.] (C) Ratios of the BMDL^ to the [SNCD.sub.0.5.] BMDL, lower confidence limit of the benchmark dose; SNCD, signal-to-noise crossover dose.
Caption: Figure 3. Histograms for the ratios [BMDL.sub.e]:[SNCD.sub.0.67] (BMDLs are based on extra effect) with medians closest to 1 based on all included curves (n = 8,456). BMDL, lower confidence limit of the benchmark dose; SNCD, signal-to-noise crossover dose.
Caption: Figure 4. Ratios of the BMDLa to the SNCD with BMDLs defined in terms of additional effects of 5%, 10%, 15%, 20%, and 25%. Ratios are given in terms of medians (solid circles) and intervals describing the lower 5th and upper 95th percentiles, based on different stratifications of the data. Red (large) circles correspond to results based on all selected curves (n = 8,456); blue circles correspond to results based on cytotoxicity assays (n = 3,130); yellow circles correspond to results based on nuclear receptor assays (n = 4,603); and cyan circles are results based on stress response assays (n = 723). (4) Ratios of the [BMDL.sub.a] to the [SNCD.sub.1.0]. (B) Ratios of the [BMDL.sub.a] to the [SNCD.sub.0.67]. (C) Ratios of the BMDLa to the [SNCD.sub.0.5]. BMDL, lower confidence limit of the benchmark dose; SNCD, signal-to-noise crossover dose.
Caption: Figure 5. Histograms of the ratios [BMDL.sub.a]:[SNCD.sub.0.67] (BMDLs are based on additional effect) with medians closest to 1 based on all included curves (n = 8,456). BMDL, lower confidence limit of the benchmark dose; SNCD, signal-to-noise crossover dose.
Caption: Figure 6. Extra effect at the SNCD. Medians (solid circles) and intervals describing the lower 5th and upper 95th percentiles are shown based on all included curves (n = 8,456). Red circles correspond to the upper bound of the effect, and cyan circles correspond to the point estimate of the effect. SNCD, signal-to-noise crossover dose.
Caption: Figure 7. Additional effect at the SNCD. Medians (solid circles) and intervals describing the lower 5th and upper 95th percentiles are based on all included curves (n = 8,456). Red circles correspond to the upper bound of the effect, and cyan circles correspond to the point estimate of the effect. BMDL, lower confidence limit of the benchmark dose; SNCD, signal-to-noise crossover dose.
Table 1. Data sets used in the analysis.
on PubChem; NTP, National Toxicology Program.
of fitting a sigmoidal (four-parameter) model such as the Hill model.
Table 2. Comparison of BMDLs and SNCDs for NTP duplicates.
departure; SNCD, signal-to-noise crossover dose.
The analysis is based on 307 duplicates (614 individual curves).
calculated such that they are always > 1 (max value/min value).
(a) Ratio of extra effect BMDLs between duplicates.
(b) Ratio of additional effect BMDLs between duplicates.
(c) Ratio of SNCDs between duplicates.
analysis of merged duplicates ([SNCD.sub.merged]).
(e) Fraction of curves for which the ratio is > 1.
Differential activation of a mouse estrogen receptor [beta] isoform (mER[beta]2) with endocrine-disrupting chemicals (EDCS).
Reassessing the link between airborne arsenic exposure among anaconda copper smelter workers and multiple causes of death using the parametric...Third Trimester Of Pregnancy: What To Eat And Exercise
The third trimester of pregnancy is the most difficult period for expecting mothers. The baby is due any moment and utmost care must be taken of the mother’s health to prevent any untoward incidents.
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