The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 229

O

OH

O OH

O

O

(c)

[VI]

[V]

O

HOH 2 C CH 2 OH

HOH 2 C

COOH

(a)

O

O O

[II]

[I] [III]

(b)

+H 2 O

2 O

O

O

O

[IV]

FIGURE 5.1 Suggested metabolic pathways of 1,4-dioxane in the rat. I = 1,4-dioxane; II = DEG; III =
β-hydroxyethoxy acetic acid (HEAA); IV = 1,4-dioxane-2-one; V = 1,4-dioxane-2-ol; VI = β-hydroxyethoxy
acetaldehyde. (Adapted from Woo, Y., Argus, M.F., and Arcos, J.C., 1977c, Biochemical Pharmacology 25:
1539-1542. With permission.)

extensive after inhalation exposure. Urinary levels of HEAA were 3000-fold higher than urinary
1,4-dioxane concentrations after exposure to 50 ppm for 6 h (Young et al., 1978a,b). 1,4-Dioxane
metabolism was shown to be a saturable process, as demonstrated by oral and i.v. exposures to
various doses of 1,4-dioxane in rats (Young et al., 1978a,b). In rats given radiolabeled 1,4-dioxane
via gavage in distilled water as single doses of 10, 100, or 1000 mg/kg or in 17 daily doses of 10 or
1000 mg/kg, the urinary excretion of radiolabeled metabolites decreased signii cantly with increas-
ing dose, while the radiolabel detected in expired air increased (i.e., exhalation of unmetabolized
1,4-dioxane).
1,4-Dioxane is primarily eliminated as HEAA in the urine; however, the exhalation of 1,4-
dioxane in breath increases at higher doses because of metabolic saturation. In workers exposed to
a TWA of 0.6 ppm for 7.5 h, 99% of 1,4-dioxane eliminated in urine was in the form of HEAA
(Young et al., 1976). The elimination half-life was 59 min in male volunteers exposed to 50 ppm
1,4-dioxane for 6 h (Young et al., 1977). As in humans, the elimination half-life in rats exposed to
50 ppm 1,4-dioxane for 6 h was calculated to be 1.01 h (Young et al., 1978a,b). After oral exposure
to rats, urinary elimination ranged from 76% to 99%, depending on the dose (i.e., urinary elimina-
tion was decreased at higher doses). Elimination of 1,4-dioxane in expired air increased with
increasing dose. Fecal elimination was less than 2% for all doses (Young et al., 1978a,b).
PBPK models are quantitative computer models that describe the movement and fate of chemi-
cals in the body. PBPK models can be used to account for the saturation of 1,4-dioxane metabolism
at high doses and adjust for differences in physiology and metabolism between humans and rats.
Two PBPK models were previously used for 1,4-dioxane risk assessment (Leung and Paustenbach,
1990; Reitz et al., 1990). These models simulated exposure via i.v., inhalation, and oral pathways.
1,4-Dioxane intake from drinking water was simulated by assuming rapid absorption of the chemi-
cal from the gastrointestinal tract directly to the liver. Uptake from air was modeled by assuming
rapid equilibration between alveolar air * and pulmonary capillary blood. Blood leaving the lungs
was distributed to four compartments including liver, fat, slowly perfused tissues such as muscle and
skin, and richly perfused tissues such as kidney, brain, and viscera. † The models incorporated

* Alveolar air is air held in the alveolar air spaces of the lung.
† Perfusion refers to forcing a l uid through an organ or tissue, especially by way of the blood vessels.