The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 242

or 5000 ppm for two years (estimated daily doses were 0, 16, 81, or 398 mg/kg in male rats and 0,
21, 103, or 514 mg/kg in female rats). Groups of Crj:BDF 1 mice (50 per sex per dose level) were
similarly exposed to 0, 500, 2000, or 8000 ppm of 1,4-dioxane in the drinking water (estimated
daily doses were 0, 66, 251, or 768 mg/kg in male mice and 0, 77, 323, or 1066 mg/kg in female
mice). Survival was signii cantly decreased in the high-dose rat groups during the second year of
the study. Neither food nor water consumption was signii cantly affected by treatment; however,
terminal body weights were reduced in high-dose rats. Hematological changes observed in rats were
generally within 15% of control values, with the exception of a 23% decrease in hemoglobin in high-
dose male rats and a 27% increase in platelets in high-dose female rats. Signii cant changes in
serum-chemistry parameters occurred only in high-dose rats [males: increased phospholipids, activ-
ity of the enzymes ALT, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline
phosphatase (ALP), -glutamyl transpeptidase (GGT), creatinine phosphokinase (CPK), potassium,

and inorganic phosphorus and decreased total protein, albumin, and glucose; females: increased
total bilirubin, * cholesterol, phospholipids, AST, ALT, LDH, GGT, ALP, CPK, and potassium, and
decreased blood glucose]. Increases in serum enzyme activities ranged from

γ

2-17-fold above con-
trol values; the largest increases were seen for ALT, AST, and GGT. Blood samples were collected
only at the end of the two-year study, so altered serum chemistry in high-dose animals may be asso-
ciated with the tumorigenic changes observed in the liver (see below).
In males, relative liver weights were increased in the high-dose group; in females, relative lung,
liver, and kidney weights were increased at the highest dose tested. Microscopic examination of the
tissues showed alterations in the nasal cavity, liver, and kidneys mainly in high-dose rats and in a
few mid-dose rats. Epithelial cells lining the nasal cavity were changed in size and appearance, and
inl ammation and proliferation of the nasal gland were observed. Liver lesions included spongiosis
hepatis, † hyperplasia, cyst formation, and clear and mixed-cell foci. ‡ The only observable change in
the kidney was nuclear enlargement of renal proximal tubule cells. Signii cantly increased inci-
dences of liver tumors (adenomas and carcinomas) and tumors of the nasal cavity occurred in high-
dose male and female rats treated with 1,4-dioxane for two years. In addition, signii cant increases
in the incidences of mesothelioma § of the peritoneum, mammary gland i broadenoma, and i broma
of the subcutis ¶ were seen in high-dose male rats. High-dose females showed a signii cant increase
in the incidence of mammary gland adenomas.
In the study in mice, survival was low in all male groups and particularly low in high-dose females.
Deaths occurred primarily during the second year of the study. Food consumption was not signii -
cantly affected, but water consumption was reduced in high-dose male and female mice. Final body
weights were reduced 43% in high-dose males and 15% and 45% in mid- and high-dose females,
respectively. Hematological changes were within 15% of control values with the exception of a 60%
decrease in platelets in high-dose female mice. Serum activities of the enzymes AST, ALT, LDH, and
ALP were signii cantly increased in mid- and high-dose males, whereas leucine aminopeptidase
(LAP) and CPK activities were increased only in high-dose males. AST, ALT, LDH, and ALP activi-
ties were increased in mid- and high-dose females, but CPK activity was increased only in high-dose
females. Increases in serum enzyme activities ranged from less than two- to sevenfold above control
values. Blood samples were collected only at the end of the two-year study, so altered serum chemis-
try in high-dose animals may be associated with the tumorigenic changes observed in the liver.
Glucose and triglycerides were decreased in high-dose males and in mid- and high-dose females.
High-dose females also showed decreases in serum phospholipid and albumin concentrations (not

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* Bilirubin is the orange-yellow pigment formed in the liver by the breakdown of hemoglobin and excreted in bile.
† Spongiosis hepatis is a cyst-like lesion that arises from the perisinusoidal Ito cells of the liver.
‡ Such foci represent preneoplastic changes in the liver.
§ Mesothelioma is a tumor of the pleura, peritoneum, or pericardium.
¶ Fibroadenoma is a tumor formed of mixed i brous and glandular tissue; i broma of the subcutis is a benign i brous tumor
in the loose connective fatty tissue found under the dermis (skin).