Dataset Information

Comparison of Points of Departure for Health Risk Assessment Based on High-Throughput Screening Data.

ABSTRACT:

Background

The National Research Council's vision for toxicity testing in the 21st century anticipates that points of departure (PODs) for establishing human exposure guidelines in future risk assessments will increasingly be based on in vitro high-throughput screening (HTS) data.

Objectives

The aim of this study was to compare different PODs for HTS data. Specifically, benchmark doses (BMDs) were compared to the signal-to-noise crossover dose (SNCD), which has been suggested as the lowest dose applicable as a POD.

Methods

Hill models were fit to > 10,000 in vitro concentration-response curves, obtained for > 1,400 chemicals tested as part of the U.S. Tox21 Phase I effort. BMDs and lower confidence limits on the BMDs (BMDLs) corresponding to extra effects (i.e., changes in response relative to the maximum response) of 5%, 10%, 20%, 30%, and 40% were estimated for > 8,000 curves, along with BMDs and BMDLs corresponding to additional effects (i.e., absolute changes in response) of 5%, 10%, 15%, 20%, and 25%. The SNCD, defined as the dose where the ratio between the additional effect and the difference between the upper and lower bounds of the two-sided 90% confidence interval on absolute effect was 1, 0.67, and 0.5, respectively, was also calculated and compared with the BMDLs.

Results

The BMDL₄₀, BMDL₂₅, and BMDL₁₈, defined in terms of extra effect, corresponded to the SNCD_1.0, SNCD_0.67, and SNCD_0.5, respectively, at the median. Similarly, the BMDL₂₅, BMDL₁₇, and BMDL₁₃, defined in terms of additional effect, corresponded to the SNCD_1.0, SNCD_0.67, and SNCD_0.5, respectively, at the median.

Conclusions

The SNCD may serve as a reference level that guides the determination of standardized BMDs for risk assessment based on HTS concentration-response data. The SNCD may also have application as a POD for low-dose extrapolation.

SUBMITTER: Sand S

PROVIDER: S-EPMC5381992 | biostudies-literature |

REPOSITORIES: biostudies-literature

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