The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 241

588-635 g (estimated daily dose range of 944-1019 mg/kg). All animals were sacrii ced within
28 months, but the scope of the postmortem examination was not reported.
Nine treated guinea pigs showed peri- or intrabronchial epithelial hyperplasia * and nodular
mononuclear ini ltration in the lungs. Four control guinea pigs had peripheral mononuclear cell
accumulation in the lungs, and only one had hyperplasia of the bronchial epithelium. Also, two
guinea pigs had carcinoma of the gall bladder, three had early hepatomas, † and one had an adenoma
of the kidney. No further information was presented in the brief narrative of this study.
Kociba et al. (1974) administered 1,4-dioxane to Sherman rats (60 per sex per dose level) via the
drinking water at concentrations of 0% (controls), 0.01%, 0.1%, or 1.0% for as long as 716 days
(approximate daily doses of 0, 9.6, 94, and 1015 mg/kg for male rats and 0, 19, 148, and 1599 mg/kg
for female rats). Treatment with 1,4-dioxane signii cantly increased mortality among high-dose
males and females beginning at about two to four months of treatment. These rats showed degenera-
tive changes in both the liver and kidneys. At termination, the only alteration in organ weights noted
by the authors was a signii cant increase in absolute and relative liver weights in male and female
high-dose rats. Histopathological lesions were restricted to the liver and kidney from the mid- and
high-dose groups and consisted of variable degrees of renal tubular epithelial and hepatocellular
degeneration and necrosis. Rats from these groups also showed evidence of hepatic regeneration, as
indicated by hepatocellular hyperplastic nodule formation and evidence of renal tubular epithelial
regenerative activity (observed after two years of exposure). An increase in the incidence of liver
tumors (hepatocellular carcinomas) and nasal carcinomas (squamous cell carcinoma of the nasal
turbinates) occurred in high-dose male and female rats. ‡
The National Cancer Institute (NCI, 1978) made a study of groups of Osborne-Mendel rats (35
per sex per dose) and B6C3F 1 mice (50 per sex per dose) that were administered 1,4-dioxane in the
drinking water for 110 or 90 weeks, respectively, at levels of 0%, 0.5%, or 1% (estimated daily doses:
0, 240, and 530 mg/kg in male rats; 0, 350, and 640 mg/kg in female rats; 0, 720, and 830 mg/kg in
male mice; and 0, 380, and 860 mg/kg in female mice). Mortality was signii cantly increased in
treated rats, beginning at approximately one year into the study. Histopathological lesions associ-
ated with 1,4-dioxane treatment were seen in the kidneys, liver, and stomach. Kidney lesions con-
sisted of vacuolar degeneration and/or focal tubular epithelial regeneration in the proximal cortical
tubules and occasional hyaline casts. Elevated incidence of liver cell enlargement also occurred in
treated female rats, and gastric ulcers occurred in treated males. The incidence of pneumonia was
increased above controls in high-dose female rats. 1,4-Dioxane treatment was associated with nasal
cavity tumors (squamous cell carcinomas, adenocarcinomas, and one rhabdomyoma) § in both sexes
and liver tumors (hepatocellular adenomas) in female rats only.
Mortality was signii cantly increased in female mice beginning at approximately 80 weeks in the
study. 1,4-Dioxane produced an increase in the incidence of mice with pneumonia (males and
females) and rhinitis ¶ (females only). A dose-related increase was also seen in the incidence of hepa-
tocellular carcinomas or adenomas in male and female mice. Tumors were characterized by paren-
chymal cells (the cells composing the bulk of the organ) of irregular size and arrangement and were
often enlarged with hyperchromatic (densely staining) nuclei. Neoplasms were locally invasive
within the liver, but metastasis to the lungs was rarely observed. **
In a study reported by JBRC (1998c) and Yamazaki et al. (1994), groups of F344/DuCrj rats (50
per sex per dose level) were exposed to 1,4-dioxane in the drinking water at levels of 0, 200, 1000,
* Hyperplasia is an increase in the reproduction rate of cells, sometimes seen as an initial stage in the development of
cancer.
† Hepatomas are liver tumors.
‡ Nasal turbinates are the spongy bones of the nasal cavity; squamous cell carcinoma is a malignant type of tumor.
§ Rhabdomyoma is a rare benign tumor of muscle tissue.
¶ Rhinitis is inl ammation of the mucous membrane of the nose (a runny nose).
** Metastasis is the development of secondary tumors at a distance from a primary site of cancer.