Dose-response assessments for developmental toxicity. IV. Benchmark doses for fetal weight changes

Area of Science:

• Toxicology and Risk Assessment
• Developmental Toxicology
• Statistical Modeling in Environmental Health

Background:

• Current benchmark dose (BMD) applications in toxicology primarily focus on quantal (all-or-none) responses.
• Appropriate modeling of continuous response measures is crucial for fully leveraging BMD in risk assessment.
• Fetal weight is a key continuous endpoint in developmental toxicity studies.

Purpose of the Study:

• To evaluate various approaches for estimating BMDs for changes in fetal weight following chemical exposure.
• To compare BMD estimates derived from continuous data with traditional NOAELs (No Observed Adverse Effect Levels).
• To confirm the advantages of the BMD approach over NOAELs in developmental toxicity risk assessment.

Main Methods:

• Analyzed 85 developmental toxicity experiments using continuous power models for mean litter weight and log-logistic models for individual fetal weight reductions.
• Incorporated litter size as a covariate and considered intralitter correlations in fetus-based models.
• Investigated multiple benchmark effect (BME) definitions for both litter-based and fetus-based approaches.

Main Results:

• BMDs derived from four litter-based BMEs and two fetus-based BMEs showed high similarity to each other.
• These BMD estimates were also comparable to statistically derived NOAELs from the same datasets.
• The study confirmed the advantages of the BMD approach regarding dose spacing and selection compared to NOAELs.

Conclusions:

• The benchmark dose (BMD) concept can be effectively applied to continuous fetal weight endpoints in developmental toxicity.
• BMD provides a robust alternative to NOAELs, offering improved sensitivity to dose selection and spacing.
• These findings support the implementation of BMD for continuous data in developmental toxicity risk assessments.