The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 243

reported in males). Blood calcium was lower in high-dose females and was not reported in males.
Relative and absolute lung weights were increased in high-dose males and in mid- and high-dose
females.
Microscopic examination showed signii cant alterations in the epithelium of the respiratory tract
(i.e., nuclear enlargement, atrophy, and inl ammation), mainly in high-dose animals, although some
changes occurred in mid-dose mice. Other notable changes included nuclear enlargement of the
proximal tubule cells of the kidney and angiectasis in the liver in high-dose males. * Treatment with
1,4-dioxane resulted in an increase in the formation of liver tumors (adenomas and carcinomas) in
male and female mice. The incidence of male mice with hepatocellular carcinoma or either tumor
type (adenoma or carcinoma) was increased in the high-dose group only. In female mice, increased
incidence was observed for each liver tumor type in all treatment groups.
Giavini et al. (1985) examined the effects of 1,4-dioxane on rat reproduction. Pregnant female
Sprague Dawley rats (18-20 per dose group) were given 1,4-dioxane by gavage in water at concen-
trations of 0, 0.25, 0.5, or 1 mL/kg per day, corresponding to dose estimates of 0, 250, 500, or
1000 mg/kg per day. The chemical was administered at a constant volume of 3 mL/kg on days 6-15
of gestation. The dams † were sacrii ced with chloroform on gestation day 21, and the numbers of
corpora lutea, ‡ implantations, resorptions, and live fetuses were recorded. Fetuses were weighed and
examined for external malformations prior to the evaluation of visceral and skeletal malformations
and a determination of the degree of ossii cation (bone formation). Maternal weight gain was
reduced by 10% in the high-dose group (1000 mg/kg per day). Food consumption for this group was
5% lower during the dosing period, but exceeded control levels for the remainder of the study. No
change from control was observed in the number of implantations, live fetuses, or resorptions; how-
ever, fetal birth weight was 5% lower in the highest-dose group. 1,4-Dioxane exposure did not
increase the frequency of major malformations or minor anomalies and variants. Ossii cation of the
sternebrae § was reduced in the 1000 mg/kg per day dose group. The study authors suggested that
the observed delay in sternebrae ossii cation combined with the decrease in fetal birth weight indi-
cated a developmental delay related to 1,4-dioxane treatment.
Fairley et al. (1934) also studied rabbits, guinea pigs, rats, and mice (3-6 per species per group)
that were exposed to 1000, 2000, 5000, or 10,000 ppm of 1,4-dioxane vapor for 3 h per day,
i ve days per week, and 1.5 h on the sixth day (16.5 h per week). Animals were exposed until
death occurred or were sacrii ced at varying time periods. At the 10,000 ppm concentration, only
one animal (rat) survived a seven-day exposure. The rest of the animals (six guinea pigs, three
mice, and two rats) died within the i rst i ve exposures. Severe liver and kidney damage and acute
vascular congestion of the lungs were observed in these animals. Kidney damage was described
as patchy degeneration of the cortical tubules with vascular congestion and hemorrhage. Liver
lesions varied from cloudy hepatocyte swelling to large areas of necrosis. At 5000 ppm, mortality
was observed in two mice and one guinea pig following 15-34 exposures. The remaining animals
were sacrii ced following 3-5 weeks of exposure (three rabbits and three guinea pigs). Liver and
kidney damage in both dead and surviving animals was similar to that described for the
10,000 ppm concentration. Liver and kidney toxicities were also apparent in animals (four rab-
bits, four guinea pigs, six rats, and i ve mice) exposed to 2000 ppm for approximately 2-6 weeks.
Cortical kidney degeneration and hepatocyte degeneration and liver necrosis were observed in
animals exposed to 1000 ppm for approximately 4-12 weeks (two rabbits, three guinea pigs,
three rats, and four mice).
* Angiectasis is the abnormal dilation of blood vessels.
† A dam is a pregnant female rat.
‡ Corpora lutea are temporary endocrine structures in mammals developed from an ovarian follicle and involved in the
production of progestogens, the hormones needed to maintain the thick lining (endometrium) of the uterus; they provide
an area rich in blood vessels where zygote(s) can be implanted and develop (i.e., so that pregnancy occurs).
§ The sternebrae is a part of the sternum, the bony plate covering the center of the chest.