A physiologically based pharmacokinetic model for fluoride uptake by bone

Area of Science:

• Toxicology
• Pharmacokinetics
• Biomathematics

Background:

• Fluoride exposure is a global health concern, impacting bone health.
• Understanding fluoride's long-term metabolic fate is crucial for risk assessment.
• Existing models often lack age and sex specificity for chronic exposure scenarios.

Purpose of the Study:

• To develop and validate a sex-specific physiologically based pharmacokinetic (PBPK) model for fluoride.
• To simulate chronic fluoride exposure from birth to old age, integrating growth.
• To analyze fluoride's absorption, distribution, and elimination, focusing on bone uptake and renal excretion.

Main Methods:

• Developed a six-compartment PBPK model including lung, liver, kidney, bone (surface and inner), and perfused tissues.
• Incorporated age and body weight-dependent physiological parameters.
• Validated the model using experimental data from rats and humans following oral fluoride intake.

Main Results:

• The model accurately describes fluoride kinetics, including bone deposition and slow release.
• It simulates the influence of growth and physiological changes on fluoride distribution.
• Predictions align with experimental data for both rats and humans.

Conclusions:

• The PBPK model provides a robust tool for analyzing chronic fluoride exposure and its effects on bone.
• It enables prediction of long-term tissue concentrations and potential toxicity.
• Facilitates cross-species extrapolation for risk assessment under various exposure conditions.