Document M4nvz0qLy1xZ2dKrZBB2kBDdL

3 February 2009 Draft Selection Criteria to identify Key In Vivo Mammalian Studies that Inform Dose-Response Modeling for 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)a Study Feature Chemical, purity, matrix/medium Peer review Study design, execution, and reporting Study subject: species, strain, and sensitivity for given endpoint; litter; life stage; gender Exposure route Dose level Exposure frequency, duration, and timing Controls Response Statistical evaluation Selection Rationale Primary*3 Secondary^ TCDD-only doses included, purity specified, TCDD purity or matrix not clearly identified matrix in which TCDD is administered is identified Independently peer-reviewed, publicly available Supplementary materials accompanying peer-reviewed publication Clearly documented and consistent with standard Testing protocol provides incomplete toxicological principles, testing protocols, coverage of relevant endpoint-specific and practice (i.e., endpoint-appropriate, measures, particularly for negative findings particularly for negative findings) Mammalian species Mammalian species, in vivo, but only Strain and gender identified studying an artificially sensitive subject Animal age at beginning of treatment identified (e.g., knockout mouse) Litter confounders (within/between) accounted for Currently Excluded Studies of dioxin-like compounds (DLCs) or mixtures Not formally peer-reviewed; literature not publicly available Studies not meeting standard principles and practices Non-mammalian or not in vivo Oral Parenteral (e.g., intravenous, intramuscular, Inhalation, dermal, ocular intraperitoneal, subcutaneous) Lowest dose <200 ng/kg-d for noncancer endpoints and <1 ^g)/kg-d for cancer Lowest dose >200 ng/kg-d for noncancer endpoints, or >1.0 ^.g/kg-d for cancer Dosing regimen characterized and explained Characterization/explanation missing or cannot be determined Appropriate and well characterized Effect reported, but with no negative control Effect relevant to human health Magnitude outside range of normal variability Precursor effects, or adaptive responses Lethality potentially relevant to human health Clearly described and appropriate to the endpoint Limited statistical context and study design (e.g., per error variance, magnitude of effect) a NAS (2006) commented that the selection of data sets for quantitative dose-response modeling needed to be more transparent. These draft criteria are offered for consideration at the kickoff workshop. These criteria would be used to identify candidate studies of non-human mammals that would be used to define the point-of-departure (POD). These criteria are not designed for hazard identification or weight-of-evidence determinations. Studies addressing data other than direct TCDD dose-response in mammals (including toxicokinetic data on absorption, distribution, metabolism, or elimination; information on physiologically-based pharmacokinetic [PBPK] modeling, and mode of action data) will be evaluated separately. b Presents preliminary draft criteria for evaluating a study being considered for estimating a POD in a TCDD dose-response model. c Presents preliminary draft criteria that could qualify a study as primary with support from other lines of evidence (e.g., PBPK modeling), when no study for an endpoint meets the "primary" criteria .