Quantitative and qualitative concordance between clinical and nonclinical toxicity data

Area of Science:

• Toxicology
• Pharmacology
• Biomedical Science

Background:

• Rodent toxicity testing is crucial for assessing chemical hazards but human concordance is difficult to evaluate.
• Existing methods face challenges in predicting human health effects from animal models.
• Understanding the predictivity of animal models is essential for regulatory science and drug development.

Purpose of the Study:

• To quantitatively and qualitatively assess the concordance between rodent toxicity data and human clinical trial outcomes.
• To compare the predictive accuracy of in vivo rodent models and in vitro assays against human health responses.
• To establish objective expectations for alternative toxicity testing approaches.

Main Methods:

• Comparison of lowest observed adverse effect levels (LOAEL) and adverse endpoints between rodent models and human clinical trials.
• Calculation of rodent human equivalent dose-adjusted LOAEL (LOAELHED) and in vitro bioactivity administered equivalent dose (AED) values.
• Statistical analysis of quantitative correlation and qualitative accuracy in predicting human effects.

Main Results:

• Rodent LOAELHED values showed moderate correlation with human LOAEL values, but quantitative dose correlation did not improve when effects were matched.
• Qualitative prediction of matched effects was low, indicating limited predictivity of rodent models.
• In vitro bioactivity AED values demonstrated similar moderate correlation but were consistently lower than human LOAEL values.
• In vitro models showed lower correlation and larger differences when compared to rodent LOAELHED values.

Conclusions:

• Rodent toxicity testing exhibits limited predictivity for human adverse effects, despite moderate dose correlations.
• In vitro alternative testing methods show comparable, yet also limited, predictive capabilities.
• The study provides objective benchmarks for evaluating the reliability of rodent and alternative toxicity testing strategies.