The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 237

the LOAEL dose are described. Carcinogenic i ndings, including the target organ, tumor type, and
the lowest dose producing a signii cant increase in tumors, are also indicated for chronic studies.
Longer-term inhalation studies consisted of only one subchronic study (Fairley et al., 1934) and one
chronic study (Torkelson et al., 1974) (both discussed here).
As reported by Fairley et al. (1934), six rats and six mice (unspecii ed strains) were given drink-
ing water containing 1.25% 1,4-dioxane for as long as 67 days (approximate daily doses were 1900
and 3300 mg/kg), respectively. Gross pathology and histopathology were evaluated in all animals.
Five of the six rats in the study died or were sacrii ced at the point of death (in extremis) prior to day
34 of the study. Mortality was lower in mice; i ve of six mice survived up to 60 days. Kidney
enlargement and renal cortical degeneration were observed in rats and mice. Large areas of necrosis
were observed in the cortex, whereas cell degeneration in the medulla was slight or absent. Tubular
casts * were observed and vascular congestion † and hemorrhage were present throughout the kidney.
Hepatocellular degeneration with vascular congestion was also noted in rats and mice.
In a study by Stott et al. (1981), male Sprague Dawley rats (4-6 per group) were given average
daily doses of 0, 10, or 1000 mg/kg 1,4-dioxane in their drinking water, seven days per week for
11 weeks. An increase in the liver-to-body-weight ratio and minimal centrilobular hepatocyte swelling
were observed in rats from the high-dose group. Hepatic DNA synthesis, measured by incorporation
of the tritium-labeled DNA nucleoside thymidine [( 3 H)-thymidine], was increased 1.5-fold in high-
dose rats. No changes relative to the control were observed for rats exposed to 10 mg/kg per day.
The JBRC administered 1,4-dioxane in the drinking water to groups of six-week-old F344/DuCrj
rats (10 per sex per group) and Crj:BDF 1 mice (10 per sex per group) for 13 weeks (JBRC, 1998b).
The concentrations of 1,4-dioxane in the water for rats and mice were 0, 640, 1600, 4000, 10,000,
or 25,000 ppm. On the basis of drinking-water ingestion and body-weight changes, male rats
received daily 1,4-dioxane doses of approximately 0, 60, 150, 330, 760, and 1900 mg/kg, and female
rats received daily doses of 0, 100, 200, 430, 870, and 2020 mg/kg. Male mice received daily doses
of 0, 100, 260, 580, 920, or 1830 mg/kg and female mice received daily doses of 0, 170, 410, 920,
1710, or 2700 mg/kg.
One female rat in the high-dose group (2020 mg/kg per day) died, but cause and time of death
were not specii ed. Food consumption was reduced at the highest dose in rats, and i nal body weights
were reduced at the two highest-dose levels in both male and female rats. A dose-related decrease
in water consumption was observed. Hematological effects (i.e., effects on blood) were within
2-15% of control values, and serum biochemistry parameters in treated rats did not differ more than
twofold from control values. Absolute and relative kidney weights were increased in females at daily
doses of 200 mg/kg. No organ weight changes were noted in male rats. Histopathology i ndings in

rats that were related to 1,4-dioxane exposure included alterations in the nasal and tracheal epithe-
lial cells, liver lesions (hepatocyte enlargement and cytoplasmic changes), changes in the kidney
(altered appearance of proximal tubule cells), and vacuolar changes in the brain (i.e., changes in
vacuole spaces within the cytoplasm of brain cells).
One male mouse in the high-dose group (1830 mg/kg per day) died, but no information was pro-
vided regarding the cause or time of the death. Food consumption was not signii cantly reduced in
any exposure group. Final body weights were decreased in high-dose male mice, but were not sig-
nii cantly reduced (i.e., within 10% of controls) in the other male dose groups and in female mice.
A dose-related decrease in water consumption was observed in male and female mice. Hematological
changes were within 2-15% of control values. With the exception of a threefold increase in the
enzymatic activity of alanine aminotransferase (ALT) in male and female mice, serum biochemis-
try parameters in treated rats did not differ more than twofold from control values. Increases in
absolute and relative lung and kidney weights were seen in male and female mice. Histopathology

≥

* Tubules in the kidneys secrete proteins; when kidney function is impaired, these proteins can precipitate and i ll the
tubules. The small cylindrical shapes that result and that can be seen under light microscopy are called casts.
† Vascular congestion is a condition in which the blood vessels become engorged with blood.