The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 252

eightfold above control values at doses of 840, 2550, and 4200 mg/kg, respectively. The results of
this study demonstrated that hepatic DNA damage can occur in the absence of signii cant cytotoxic-
ity. The fact that parameters associated with tumor promotion (i.e., ODC activity, CYP450 content)
were also elevated suggests that promotion may play a role in the carcinogenesis of 1,4-dioxane.
5.4 SUMMARY OF NONCANCER HEALTH EFFECTS
Liver and kidney toxicities were the primary noncancer health effects associated with exposure to
1,4-dioxane in humans and laboratory animals. Several fatal cases of hemorrhagic nephritis and
centrilobular necrosis of the liver were related to occupational exposure to 1,4-dioxane (Barber,
1934; Johnstone, 1959). Neurological changes were also reported in one case, including headache,
elevation in blood pressure, agitation and restlessness, and coma (Johnstone, 1959). Perivascular
widening was observed in the brain of this worker, with small foci of demyelination in several
regions (e.g., cortex and basal nuclei). Severe liver and kidney degeneration and necrosis were
observed frequently in acute oral and inhalation studies (Fairley et al., 1934; de Navasquez, 1935;
Schrenk and Yant, 1936; Kesten et al., 1939; Laug et al., 1939; David, 1964; Drew et al., 1978;
JBRC, 1998a).
Liver and kidney toxicities were the primary noncancer health effects of subchronic and chronic
oral exposure to 1,4-dioxane in animals. Liver effects included degeneration and necrosis, hepato-
cyte swelling, cells with hyperchromic nuclei, spongiosis hepatis, hyperplasia, and clear and mixed-
cell foci of the liver (Fairley et al., 1934; Argus et al., 1965, 1973; Kociba et al., 1974; NCI, 1978;
JBRC, 1998c). Liver hyperplasia and clear and mixed-cell foci are commonly considered precancer-
ous changes and would not be considered evidence of noncancer toxicity. Spongiosis hepatis may
also occur in combination with preneoplastic foci or hepatocellular adenoma or carcinoma (Stroebel
et al., 1995; Bannasch, 2003). Hepatocellular degeneration and necrosis were seen at high doses in
a subchronic study (1900 mg/kg per day in rats) (Fairley et al., 1934) and at lower doses in a chronic
study (94 mg/kg per day, male rats) (Kociba et al., 1974).
Kidney damage at high doses was characterized by degeneration of the cortical tubule cells,
necrosis with hemorrhage, and glomerulonephritis (Fairley et al., 1934; Argus et al., 1965, 1973;
Kociba et al., 1974; NCI, 1978). Renal cell degeneration generally began with cloudy swelling of
cells in the cortex (Fairley et al., 1934). Nuclear enlargement of proximal tubule cells was observed
at doses below those producing renal necrosis (JBRC, 1998b,c), but is of uncertain toxicological
signii cance. The lowest daily dose reported to produce kidney damage was 94 mg/kg, which pro-
duced renal degeneration and necrosis of tubule epithelial cells in male rats (Kociba et al., 1974).
Cortical tubule degeneration was seen at higher daily doses in the NCI (1978) bioassay (240 mg/kg,
male rats), and glomerulonephritis was reported for rats given daily doses of at least 430 mg/kg
(Argus et al., 1965, 1973).
Exposure to 1,4-dioxane in the drinking water resulted in effects on nasal cavity and respiratory
tract tissues in mice and rats (NCI, 1978; JBRC, 1998c). Rhinitis and inl ammation of the nasal
cavity were reported, as well as atrophy of the nasal epithelium and adhesion in rats and mice.
Nasal inl ammation may be a response to direct contact of the nasal mucosa with drinking water
containing 1,4-dioxane (Goldsworthy et al., 1991; Sweeney et al., 2008). Metaplasia and hyper-
plasia of the nasal epithelium were also observed in high-dose male and female rats (JBRC,
1998c); however, these effects are likely to be associated with the formation of nasal cavity tumors
in these dose groups. Nuclear enlargement of the nasal olfactory epithelium was also observed;
however, it is unclear whether this alteration represents an adverse toxicological effect. A signii -
cant increase in the incidence of pneumonia was reported in mice from the NCI (1978) study. The
signii cance of this effect is unclear, as it was not observed in other studies that evaluated lung his-
topathology (Kociba et al., 1974; JBRC, 1998b,c). Nuclear enlargement of the tracheal and bronchial
epithelium and an accumulation of foamy cells in the lung were also seen in male and female mice
(JBRC, 1998c).