Pharmacokinetics of 1,4‐dioxane in humans

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Abstract
The pharmacokinetics and metabolism of 1,4-dioxane [a widely used industrial solvent] were determined in 4 healthy male volunteers exposed to 50 ppm dioxane vapor for 6 h. Samples of blood and urine collected during and after the exposure were analyzed for dioxane and its metabolite .beta.-hydroxyethoxyacetic acid (HEAA) by gas chromatography-mass spectrometry. A pharmacokinetic model with associated parameters was constructed to describe the fate of dioxane and HEAA in humans. The model was compared to a model constructed previously for dioxane in rats. This comparison facilitates assessment of the hazard to humans of dioxane exposure by extrapolation of toxicological information obtained in rats. The dynamics of dioxane uptake and elimination in humans could be described by a 1-compartment open-system model with 0-order uptake and 1st-order elimination. The half-life for elimination of dioxane was 59 .+-. 7 min; 99.3% of the elimination was by metabolism of dioxane to HEAA, and 0.7% was by excretion of dioxane in the urine. Dioxane and HEAA were detectable in the urine until 6 and 18 h after cessation of exposure, respectively. The total absorbed dose of dioxane during the 6 h period was 5.4 .+-. 1.1 mg/kg, although the maximum amount of dioxane in the body at any one time was 1.2 .+-. 0.2 mg/kg and occurred at the end of the exposure. At 6 h the amount of dioxane in the body had reached over 99% of the steady-state amount. A simulation of repeated daily exposures to 50 ppm dioxane for 8 h/day indicated that dioxane would never accumulate to concentrations above those attained after a single 8 h exposure as long as the exposure concentration of dioxane was 50 ppm or less. Lack of accumulation of dioxane on repeated exposure is a critical point since saturation of the metabolism of dioxane at high dosage levels to rats led to toxicity. Exposure to the current threshold limit value of 50 ppm dioxane in the workplace will probably not cause adverse effects, even when the exposure is on a continuous or repeated basis.