Choice of morphometric methods and consequences in the regulatory environment

Area of Science:

• Toxicology
• Histopathology
• Stereology

Background:

• Quantitative tissue structural data, particularly cell number, is vital for drug development and risk assessment.
• Routine histopathology methods for estimating cell number have limitations in sensitivity and accuracy.
• Existing industry practices for cell counting in regulatory toxicology need robust, statistically sound alternatives.

Purpose of the Study:

• To discuss the limitations of traditional cell counting methods in histopathology for regulatory toxicology.
• To contrast these limitations with the advantages of design-based stereology.
• To advocate for the implementation of unbiased stereological methods in regulatory settings.

Main Methods:

• Review of existing industry practices for cell number estimation.
• Discussion of scientific and regulatory perspectives on histopathological limitations.
• Highlighting advances in stereological theory, software, hardware, and automated staining.

Main Results:

• Standard cell or nuclear profile counts from routine histopathology are insufficient for detecting small changes in cell number.
• Design-based stereology provides robust, sensitive, and statistically based methods for cell quantification.
• Recent technological advancements make unbiased stereology feasible for regulatory toxicology.

Conclusions:

• Design-based stereology is recommended for quantifying cell number when small changes are critical for risk assessment.
• These methods offer superior sensitivity and statistical accuracy compared to other tissue section-based methodologies.
• Implementation of unbiased stereological methods enhances the reliability of toxicological decision-making.