Benchmark Response (BMR) Values for In Vivo Mutagenicity Endpoints

Area of Science:

• Toxicology
• Genotoxicity Testing
• Risk Assessment

Background:

• The benchmark dose (BMD) approach is crucial for risk assessment and regulatory decisions.
• Defining appropriate benchmark response (BMR) values for genotoxicity is controversial.
• Existing BMRs lack standardization for in vivo mutagenicity assays.

Purpose of the Study:

• To apply Effect Size (ES) theory to derive robust BMR values for in vivo transgenic rodent (TGR) and Pig-a mutagenicity endpoints.
• To investigate the influence of experimental factors on within-group variance (var) for these endpoints.
• To recommend a standardized BMR for in vivo mutagenicity risk assessment.

Main Methods:

• Utilized Slob (2017) ES theory to define BMR values.
• Curated an extensive database of dose-response data for TGR and Pig-a assays.
• Performed BMD analyses to determine endpoint-specific maxima (c) and variance (var).
• Assessed the impact of tissue, administration route, duration, and sampling time on var.
• Calculated BMRs using both typical var and trimmed SD of concurrent controls.

Main Results:

• Experimental factors showed minimal influence on within-group variance (var).
• Typical var values were 0.19 for TGR and 0.29 for Pig-a.
• Endpoint-specific BMRs calculated using var were 47% (TGR) and 60% (Pig-a).
• BMRs calculated using trimmed SD were 33% (TGR) and 58% (Pig-a).

Conclusions:

• A consistent BMR value is recommended for in vivo mutagenicity endpoints.
• A 50% BMR is proposed for interpreting mutagenicity dose-response data in risk assessments.
• This standardized BMR enhances consistency and pragmatism in genotoxicity risk evaluation.