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Summary
This summary is machine-generated.

Establishing a consistent Benchmark Response (BMR) for error-corrected sequencing (ECS) mutagenicity testing is crucial for accurate risk assessment. This study proposes a 30% BMR for in vivo ECS technologies, enhancing dose-response modeling and human health evaluations.

Keywords:
HAWK‐seqPECC‐seqPROASTPacBio HiFibenchmark doseduplex sequencingeffect sizerisk assessment

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Area of Science:

  • Toxicology and Risk Assessment
  • Genetics and Genomics
  • Molecular Biology

Background:

  • The Benchmark Dose (BMD) approach is vital for risk assessment, but selecting a Benchmark Response (BMR) for continuous endpoints remains challenging.
  • Error-corrected sequencing (ECS) technologies offer advanced mutagenicity assessment, necessitating standardized BMR values for reliable interpretation.
  • Previous work established a 50% BMR for specific in vivo mutagenicity assays, highlighting the need for technology-specific BMRs.

Purpose of the Study:

  • To compare two methods for defining BMR values for ECS technologies: Effect Size (ES) theory and the one standard deviation approach.
  • To determine technology-specific within-group variance values for BMR calculations using a compiled ECS dose-response database.
  • To propose a standardized BMR for in vivo ECS mutagenicity assessment to improve consistency in risk evaluation.

Main Methods:

  • Compiled a dose-response database from various in vivo error-corrected sequencing studies.
  • Applied the Effect Size (ES) theory and the one standard deviation approach to define BMR values.
  • Examined experimental factors influencing within-group variance (var) to justify using technology-specific var values for BMR determination.

Main Results:

  • No significant influence of experimental factors (species, strain, route, time, tissue, DNA method) on within-group variance was detected.
  • Calculated technology-specific BMRs: 27.7% for Duplex Sequencing (DupSeq), 16.6% for Hawk-Seq, and 23.3% for PECC-Seq.
  • BMRs derived from negative control values ranged from 5.6% to 31.5% across different ECS technologies.

Conclusions:

  • The study supports the adoption of a 30% BMR for in vivo error-corrected sequencing mutagenicity assessment technologies.
  • A standardized BMR provides a robust and consistent foundation for future dose-response modeling in toxicology.
  • This approach will enhance the reliability of human health risk assessments based on advanced mutagenicity testing.