Development of a physiologically based pharmacokinetic model for risk assessment with 1,4-dioxane

Area of Science:

• Toxicology and Environmental Health
• Pharmacokinetics and Drug Metabolism
• Quantitative Risk Assessment

Background:

• Diethylene-1,4-dioxide (dioxane) is an environmental contaminant with potential health risks.
• Understanding dioxane's disposition and metabolic fate is crucial for risk assessment.
• Previous pharmacokinetic data existed, but a comprehensive model was lacking.

Purpose of the Study:

• To develop and validate a physiologically based pharmacokinetic (PB-PK) model for dioxane and its metabolite, beta-hydroxyethoxyacetic acid.
• To describe dioxane disposition across different species (rats, mice, humans) and exposure routes (gavage, intravenous, inhalation).
• To estimate plausible upper bounds of carcinogenic risk for human populations exposed to dioxane.

Main Methods:

• Developed a six-compartment PB-PK model incorporating experimentally determined partition coefficients.
• Validated the model against existing pharmacokinetic data from rat and human studies.
• Investigated nonlinear kinetic behavior of dioxane at high exposure concentrations.

Main Results:

• The PB-PK model accurately described dioxane and metabolite disposition in rats, mice, and humans.
• Significant nonlinearities in dioxane kinetics were observed at high exposure levels (>0.1% in water, >300 ppm in air).
• Quantitative risk assessment indicated low carcinogenic potential for humans at typical environmental exposure levels.

Conclusions:

• The developed PB-PK model provides a robust framework for understanding dioxane pharmacokinetics.
• Nonlinear kinetics at high doses suggest a threshold effect, reducing risk at lower exposures.
• Continuous human exposure to 740-3700 ppb dioxane in air or 20,000-120,000 ppb in water is unlikely to increase tumor frequency.