Prioritization and Product Stewardship
New Approach Methodologies (NAMs) include computational, in vitro, and other non-animal approaches that can provide human-relevant evidence for safety assessment.
ScitoVation integrates computational screening, transcriptomic and in vitro data, dosimetry, and exposure assessment to build tiered approaches for NAMs that help clients prioritize compounds, focus testing where it adds value, and make clearer safety and product-stewardship decisions.
Why ScitoVation: Building Tiered NAMs Strategies Around the Decision
ScitoVation does not start with a particular assay or technology. We start with the decision that needs to be made, the evidence already available, and the level of confidence required.
Our published tiered framework helps match the complexity of the methods to the question, moving from efficient screening approaches to more targeted or complex testing only where additional evidence is needed.
The framework includes four levels:
- Computational screening: To identify potential liabilities and prioritize compounds.
- High-throughput in vitro screening: To characterize biological activity across broad response pathways.
- Fit-for-purpose assays: To investigate specific modes of action and generate quantitative dose-response information.
- More complex biological systems: When additional evidence is needed to increase confidence.
Exposure and dosimetry are considered throughout, and compounds do not need to progress through every level. The next step is determined by the decision context, remaining uncertainty, and whether additional evidence is likely to change the assessment.
How We Prioritize Compounds Using Integrated NAMs
ScitoVation uses tiered, decision-led NAMs strategies to prioritize compounds based on the level of evidence needed. By combining fit-for-purpose assays, biomarkers, dosimetry, and exposure information, we help clients focus further testing where it adds the most value.
Prioritizing Estrogen-Active Compounds with Integrated NAMs
The American Chemistry Council needed a robust NAM-based approach for prioritizing estrogen-active compounds.
ScitoVation Approach
- Developed a fit-for-purpose human uterotrophic assay to generate dose-response data and points of departure.
- Used quantitative in vitro-to-in vivo extrapolation (qIVIVE) to convert active in vitro concentrations into human-equivalent doses.
- Compared bioactivity with estimated human exposure using activity-to-exposure ratios.
Client Benefit
- Increased confidence by showing assay-derived human equivalent doses were lower than or equivalent to in vivo points of departure for 83% of compounds.
- Enabled faster, risk-based compound prioritization.
- Provided a tiered framework for determining when more detailed assessment may be needed.
H3: Prioritizing Fluorocarbon Compounds with Targeted Biomarkers
Our client needed to compare potential liver and endocrine effects across several fluorinated candidate compounds.
ScitoVation Approach
- Assessed cytotoxicity and cell viability in liver and epithelial cell lines.
- Tested compounds at sub-cytotoxic concentrations.
- Used gene-expression biomarkers to evaluate PPARα and ERα activity.
Client Benefit
- Distinguished compounds with different biological activity profiles.
- Enabled rapid, cost-efficient candidate down-selection.
- Helped focus further testing on the most relevant compounds.
Using Transcriptomic Points of Departure for Early Prioritization
Our client needed to better understand acetamide’s mode of action and establish a scientifically supported point of departure.
ScitoVation Approach
- Analyzed whole-transcriptome responses across multiple doses and exposure durations.
- Applied pathway and gene-set analyses to investigate mode of action.
- Used transcriptomic benchmark-dose modeling and compared resulting PODs with traditional apical endpoints.
Client Benefit
- Increased confidence through consistency across transcriptomic approaches.
- Strengthened the assessment through concordance with traditional endpoints.
- Provided a reference point that could support formal human-health risk assessment.
How We Support Product Stewardship with NAMs Evidence
ScitoVation integrates NAMs, dosimetry, and exposure modeling to help teams evaluate safety questions across the product lifecycle.
Within a tiered approach, we help determine when available evidence is sufficient for a decision and when additional refinement is needed for specific exposures or susceptible populations.
Using Human Airway Models and Dosimetry for Inhalation-Risk Decisions
We helped our client by evaluating whether human airway models and computational dosimetry could predict point-of-contact inhalation toxicity.
ScitoVation Approach
- Exposed human airway models representing five regions of the respiratory tract to 1,3-dichloropropene.
- Measured epithelial barrier integrity and cytotoxicity following exposure.
- Used airway dosimetry modeling to translate in vitro effects into equivalent inhaled exposure levels and compared predictions with in vivo points of departure.
Client Benefit
- Increased confidence by showing NAM-based predictions were qualitatively consistent with in vivo findings.
- Clarified how equivalent exposure differed across respiratory regions.
- Provided a tiered framework for deciding when more targeted testing may be needed.
Assessing Risk Across Susceptible Populations
Our client needed to understand whether age and renal impairment could alter internal exposure and require additional consideration in the safety assessment.
ScitoVation Approach
- Developed rat and human PBPK models using in vitro metabolism and available kinetic data.
- Applied qIVIVE to predict internal exposure in adults, children, and renally impaired adults.
- Used Monte Carlo analysis and internal dose comparisons to characterize variability and calculate margins of internal exposure and safety.
Client Benefit
- Provided chemical-specific evidence for evaluating susceptible populations.
- Reduced uncertainty by accounting for population differences in pharmacokinetics.
- Helped determine whether additional refinement was needed to support a more informed safety decision.