The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 240

i ndings in mice that were related to exposure included liver lesions (cell swelling and single-cell
necrosis) and alterations in nasal and bronchial epithelial cells.
In a study by Argus et al. (1965), 26 adult male Wistar rats were exposed to 1,4-dioxane in the
drinking water at a concentration of 1% for 63 weeks (approximate daily dose of 640 mg/kg). A
group of nine untreated rats served as controls. Six of the 26 treated rats developed liver tumors
(hepatocellular carcinomas). No liver tumors were observed in control rats. In two rats that died
after 21.5 weeks of treatment, preneoplastic changes (histological changes preceding the develop-
ment of tumors) appeared to involve the entire liver. Animals killed after 60 weeks of treatment
showed small neoplastic nodules * or multifocal hepatocellular carcinomas † No cirrhosis was
observed in this study. ‡ Many rats had extensive changes in the kidneys often resembling glomerulo-
nephritis. § This effect progressed from increased cellularity to thickening of the glomerular capsule
followed by obliteration of the glomeruli.
In two later studies (Hoch-Ligeti et al., 1970; Argus et al., 1973), groups of 2-3-month-old male
Sprague Dawley rats (28-32 per dose group) were administered 1,4-dioxane in the drinking water
for as long as 13 months at concentrations of 0%, 0.75%, 1.0%, 1.4%, or 1.8% (approximate daily
doses of 0, 430, 574, 803, and 1032 mg/kg). The progression of liver tumorigenesis was evaluated by
an additional group of 10 male rats administered 1% 1,4-dioxane in the drinking water (574 mg/kg
per day), i ve of which were sacrii ced after eight months of treatment and i ve of which were killed
after 13 months of treatment.
The i rst change observed in the liver was an increase in the size of the nucleus of the hepato-
cytes, mostly in the periportal area. ¶ Precancerous changes were characterized by disorganization
of the rough endoplasmic reticulum, an increase in smooth endoplasmic reticulum, and a decrease
in glycogen and increase in lipid droplets in hepatocytes. These changes increased in severity in the
hepatocellular carcinomas in rats exposed to 1,4-dioxane for 13 months. Cirrhosis of the liver was
not observed.
Nasal cavity tumors were observed upon gross examination of six rats with tumors visible either
at the tip of the nose, bulging out of the nasal cavity, or on the back of the nose covered by intact or
later ulcerated skin. As the tumors obstructed the nasal passages, the rats had difi culty breathing
and lost weight rapidly. Neurological signs and compression of the brain were not observed. In all
cases, the tumors were squamous cell carcinomas with marked keratinization ** and formation of
keratin pearls. Bony structure was extensively destroyed in some animals with tumors, but there was
no invasion into the brain. Kidney toxicity was observed following exposure to 1,4-dioxane. Effects
included glomerulonephritis and pyelonephritis, †† with characteristic epithelial proliferation of
Bowman's capsule, ‡‡ periglomerular i brosis, and distension of tubules. No kidney tumors were
found.
Hoch-Ligeti and Argus (1970) also provided a brief account of the results of exposure of guinea
pigs to 1,4-dioxane. 1,4-Dioxane was administered to 22 male guinea pigs in the drinking water for
23-28 months. A group of 10 untreated guinea pigs served as controls. The authors stated that the
concentration of 1,4-dioxane was regulated so that normal growth of the guinea pigs was main-
tained and that the amount of 1,4-dioxane received by the guinea pigs over a 23-month period was
* A neoplasm is the abnormal proliferation of cells in tissue or organs to form a tumor.
† Multifocal hepatocellular carcinomas are cancerous cell growths at multiple locations within the liver.
‡ Cirrhosis is the replacement of liver tissue by scar tissue and regenerative nodules, leading to progressive loss of liver
function.
§ Glomerulonephritis is a kidney disease characterized by inl ammation of the glomeruli, or small blood vessels in the
kidneys.
¶ The periportal area surrounds the portal vein of the liver.
** Keratinization is the i lling of cells with the i brous proteins found in hair, nails, and claws.
†† Pyelonephritis is a bacterial infection of the kidney.
‡‡ Bowman's capsule is a capsule-shaped membrane structure surrounding the glomerulus of each mammalian kidney
tubule (nephron).