Application of new approach methodology-derived points of departure with predicted or regulatory exposures to estimate bioactivity to exposure ratios (BER) for risk assessment

New approach methodologies assays were examined with CompTox Chemicals Dashboard (CTCD) and Integrated Chemical Environment (ICE) databases that utilize two versions of invitrodb (v.4.1 and 3.5, respectively) to investigate: 1) how assay target values differed between the two versions; 2) how modeled endpoint predictions compared with in vivo endpoints; and 3) how they can be used in risk assessment. Chlorpyrifos (CPF), fipronil (FIP) and imidacloprid (IMID) with DNT/DART in vivo endpoints were examples in this case study. CTCD assays with AC50, and Benchmark Dose (BMD) endpoints and ICE assays with AC50 endpoints had DART/DNT targets for these pesticides. Z-Scores indicated chemical-target specificity. Activity ratios (FD) for the same assay (CTCD AC50/CTCD BMD, CTCD AC50/ICE AC50, ICE AC50/CTCD BMD) had 89%-FD <5. IVIVE models (3COMP, PBTK) had AC50 and BMD inputs to predict human administered equivalent doses (AEDHuman mg/kg/day) for comparison with measured in vivo lowest observed effect levels (LOEL) mg/kg/day: CPF 3.0; FIP 0.2; IMID 30. IVIVE 3COMP model had the lowest FD for AEDHuman compared to invivo LOELs. Bioactivity to Exposure (BER) ratios were then calculated by: 3COMP AEDHuman or in vivo adjusted or scaled LOELs to regulatory or modeled predictions (SEEM or biomonitoring). BERs showed safe levels.