Environmental Engineering Reference
In-Depth Information
5.5
CHARACTERIZATION OF CANCER POTENTIAL
5.5.1 S UMMARY OF H UMAN AND A NIMAL D ATA
Human studies of occupational exposure to 1,4-dioxane were generally negative; however, in each
case, the cohort size and number of reported cases were small, and the probability of detecting an
excess cancer risk was low (Thiess et al., 1976; Bufl er et al., 1978). Several carcinogenicity bioassays
have been conducted for 1,4-dioxane in mice, rats, and guinea pigs (Argus et al., 1965, 1973; Hoch-
Ligeti and Argus, 1970; Hoch-Ligeti et al., 1970; Kociba et al., 1974; Torkelson et al., 1974; NCI,
1978; JBRC, 1998c). Liver tumors have been observed following drinking-water exposure in male
Wistar rats (Argus et al., 1965), male guinea pigs (Hoch-Ligeti and Argus, 1970), male Sprague
Dawley rats (Hoch-Ligeti et al., 1970; Argus et al., 1973), male and female Sherman rats (Kociba
et al., 1974), female Osborne-Mendel rats (NCI, 1978), male and female F344/DuCrj rats (JBRC,
1998c), male and female B6C3F 1 mice (NCI, 1978), and male and female Crj:BDF 1 mice (JBRC,
1998c). In the earliest cancer bioassays, the liver tumors were described as hepatomas (Argus et al.,
1965, 1973; Hoch-Ligeti and Argus, 1970; Hoch-Ligeti et al., 1970); however, later studies made a
distinction between hepatocellular carcinoma and hepatocellular adenoma (Kociba et al., 1974; NCI,
1978; JBRC, 1998c). Both tumor types have been seen in rats and mice exposed to 1,4-dioxane.
Kociba et al. (1974) noted evidence of liver toxicity at or below the dose levels that produced liver
tumors. Hepatocellular degeneration and necrosis were observed in the mid- and high-dose groups
of male and female Sherman rats exposed to 1,4-dioxane, whereas tumors were observed only at the
highest dose. Hepatic regeneration was indicated in the mid- and high-dose groups by the formation
of hepatocellular hyperplastic nodules. JBRC (1998c) also demonstrated signs of liver hyperplasia
in male F344/DuCrj rats at a dose level below the dose that induced a statistically signii cant increase
in tumor formation. The male mouse data from the JBRC (1998c) study were confounded by a high
incidence of liver tumors in the male controls (42% incidence).
Nasal cavity tumors were also observed in Sprague Dawley rats (Hoch-Ligeti et al., 1970; Argus
et al., 1973), Osborne-Mendel rats (NCI, 1978), Sherman rats (Kociba et al., 1974), and F344/DuCrj
rats (JBRC, 1998c). Most tumors were characterized as squamous cell carcinomas. Nasal tumors
were not elevated in B6C3F 1 or Crj:BDF 1 mice. With the exception of the NCI (1978) study, the inci-
dence of nasal cavity tumors was generally lower than that of liver tumors in the same study popula-
tion. JBRC (1998c) was the only study that evaluated nonneoplastic changes in nasal cavity tissue
following prolonged exposure to 1,4-dioxane in the drinking water. Histopathological lesions in
female F344/DuCrj rats were suggestive of toxicity and regeneration in this tissue (i.e., atrophy, adhe-
sion, inl ammation, nuclear enlargement, and hyperplasia and metaplasia of respiratory and olfactory
epithelium). Some of these effects occurred at a lower daily dose (103 mg/kg) than that shown to
produce nasal cavity tumors (513 mg/kg). Goldsworthy et al. (1991) suggested that formation of nasal
cavity tumors may be related to inhalation of water droplets during drinking and may not be due to
systemic exposure to 1,4-dioxane. Reexamination of tissue sections from the NCI (1978) bioassay
suggested that the majority of nasal tumors were located in the dorsal nasal septum or the nasotur-
binate of the anterior portion of the dorsal meatus. The location of these tumors is consistent with the
possibility that inhalation of droplets of drinking water may be responsible for nasal lesions observed
following chronic exposure to 1,4-dioxane. Nasal tumors were not observed in an inhalation study in
Wistar rats exposed to 111 ppm for i ve days per week for two years (Torkelson et al., 1974).
5.5.2 W EIGHT - OF -E VIDENCE E VALUATION
The International Agency for Research on Cancer (IARC) classii es 1,4-dioxane as possibly carcino-
genic to humans (Group 2B) based on inadequate evidence in humans and sufi cient evidence in
experimental animals (IARC, 1999). Similarly, the U.S. Environmental Protection Agency (USEPA)
has classii ed 1,4-dioxane as a probable human carcinogen (Group B2) on the basis of inadequate
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