title: Comparison of Points of Departure for Health Risk Assessment Based on High-Throughput Screening Data.
abstract: 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 onin vitrohigh-throughput screening (HTS) data.
  
  
  
  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.
  
  
  
  Hill models were fit to > 10,000in vitroconcentration-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.
  
  
  
  The BMDL40, BMDL25, and BMDL18, defined in terms of extra effect, corresponded to the SNCD1.0, SNCD0.67, and SNCD0.5, respectively, at the median. Similarly, the BMDL25, BMDL17, and BMDL13, defined in terms of additional effect, corresponded to the SNCD1.0, SNCD0.67, and SNCD0.5, respectively, at the median.
  
  
  
  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.
authors.affiliation: Department of Risk Benefit Assessment, National Food Agency, Uppsala, Sweden.
authors.forename: Salomon
authors.initials: S
authors.lastname: Sand
authors.forename: Fred
authors.initials: F
authors.lastname: Parham
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Portier
authors.forename: Raymond R
authors.initials: RR
authors.lastname: Tice
authors.forename: Daniel
authors.initials: D
authors.lastname: Krewski
mesh_terms: D019985:Benchmarking; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000032:analysis / Q000592:standards* / Q000706:statistics & numerical data; D057166:High-Throughput Screening Assays; D006801:Humans; D008962:Models, Theoretical; D018570:Risk Assessment / Q000379:methods; D018675:Toxicity Tests