The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 228

in blood and urine (Young et al., 1976, 1977). Similar i ndings were reported for inhalation exposure
in rats (Young et al., 1978a,b). Gastrointestinal absorption was nearly complete in male rats admin-
istered oral doses of 10-1000 mg/kg, * given as a single dose or as 17 consecutive daily doses (Young
et al., 1978a,b). Dermal absorption data for 1,4-dioxane are limited. A study in rhesus monkeys
showed little dermal penetration from a methanol or skin lotion vehicle (Marzulli et al., 1981); how-
ever, signii cant dermal absorption was suggested by an in vitro experiment using excised human
abdominal skin and three different vehicle preparations (water, lotion, and isopropyl myristate)
(Bronaugh, 1982).
No data are available to describe the distribution of 1,4-dioxane in humans or animals after oral
or inhalation exposure to 1,4-dioxane. After an injection of radiolabeled 1,4-dioxane into the
abdominal cavity [intraperitoneal (i.p.) injection] of male Sprague Dawley rats, the tissue distribu-
tion was generally uniform across liver, kidney, spleen, lung, colon, and skeletal muscle 1, 2, 6, and
12 h later (Woo et al., 1977a). Blood concentrations were higher than tissue concentrations at all
times except for 1 h postdosing, when kidney levels were approximately 20% higher than blood. A
PBPK modeling study suggested that 1,4-dioxane may be transferred to breast milk in lactating
mothers (Fisher et al., 1997).
Covalent binding (i.e., irreversible binding) was measured in liver cells 16 h after dosing by i.p.
injection (Woo et al., 1977a). Covalent binding to cellular proteins and lipids can lead to toxicity,
and binding to deoxyribonucleic acid (DNA) may lead to mutagenesis. Binding was greatest in the
nuclear, microsomal, and mitochondrial fractions of the cell; little covalent binding was seen in the
cytoplasmic l uid of liver cells (cytosol of hepatocytes). Pretreatment of rats with mixed-function
oxidase † inducers [phenobarbital, 3-methylcholanthrene, or polychlorinated biphenyls (PCBs)] did
not signii cantly change the extent of covalent binding in subcellular fractions of hepatocytes (Woo
et al., 1977a). This i nding suggests that oxidative metabolism of 1,4-dioxane in the liver does not
lead to the formation of reactive intermediates that covalently bind to cellular constituents resulting
in toxicity.
A proposed metabolic scheme for 1,4-dioxane is presented in Figure 5.1 . The major product of
1,4-dioxane metabolism is HEAA. This metabolite could be generated from oxidation of 1,4-diox-
ane via diethylene glycol (DEG), 1,4-dioxane-2-ol, or 1,4-dioxane-2-one (Woo et al., 1977b).
Oxidation to DEG and HEAA appears to be the most likely, because DEG was found as a minor
metabolite in Sprague Dawley rat urine following a single 1000 mg/kg gavage ‡ dose of 1,4-dioxane
(Braun and Young, 1977). Additionally, i.p. injection of 100-400 mg/kg DEG in Sprague Dawley
rats resulted in urinary elimination of HEAA (Woo et al., 1977b). 1,4-Dioxane oxidation was shown
to be mediated by the cytochrome P450 (CYP) enzyme system in the liver. § CYP induction with
phenobarbital or Arochlor 1254 (a PCB mixture) and suppression with 2,4-dichloro-6-phenylphe-
noxy ethylamine or cobaltous chloride were effective in signii cantly increasing and decreasing,
respectively, the appearance of HEAA in the urine of Sprague Dawley rats (Woo et al., 1977c,
1978). 1,4-Dioxane itself induced the CYP-mediated metabolism of other compounds in laboratory
animals (Mungikar and Pawar, 1978). Nannelli et al. (2005) described the induction of several iso-
forms of CYP in hepatic, renal, and nasal tissues following exposure to 1,4-dioxane in rats.
Metabolism of 1,4-dioxane to HEAA is extensive in humans following inhalation exposure.
Workers exposed to a time-weighted average (TWA) concentration of 0.6 ppm 1,4-dioxane for
7.5 h had a ratio of 118:1 for HEAA and 1,4-dioxane concentrations measured in the urine (Young
et al., 1976). Similarly, in male volunteers exposed to 50 ppm for 6 h (Young et al., 1977), more
than 99% of inhaled 1,4-dioxane appeared in the urine as HEAA. Metabolism in rats is also
* Milligrams of 1,4-dioxane per kilogram of body weight of the subject animal.
† Mixed-function oxidase enzymes catalyze the oxidation of drugs and chemicals.
‡ Gavage is the introduction of material into the stomach by a tube.
§ Cytochrome P450 enzymes are a family of intracellular hemoprotein-containing enzymes that function in the oxidative
metabolism of drugs and chemicals.