The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 244

Finally, in a study by Torkelson et al. (1974) male and female Wistar rats (288 per sex) were
exposed whole-body to 1,4-dioxane vapors at a concentration of 0.4 mg/L (111 ppm), 7 h per day,
i ve days per week for two years. Control rats (192 per sex) were exposed to i ltered air. Exposure to
1,4-dioxane vapors had no signii cant effect on mortality or body-weight gain and induced no signs
of eye or nasal irritation or respiratory distress. Slight changes in hematological and clinical chem-
istry parameters were within the normal physiological limits and were not considered to be of toxi-
cological importance by the investigators. Organ weights were not signii cantly affected, and
microscopic examination of tissues did not reveal any treatment-related effects.
5.3.3 M ECHANISTIC T OXICOLOGY S TUDIES
5.3.3.1 Genotoxicity
Weight-of-evidence evaluations of the genetic toxicity data have concluded that 1,4-dioxane is either a
very weak genotoxin (Kitchin and Brown, 1990; Ashby, 1994) or not genotoxic (NICNAS, 1998;
Netherlands Organization for Applied Scientii c Research, 1999). The genotoxicity data for 1,4-dioxane
are presented in Table 5.4 . Negative i ndings were reported for mutagenicity in assays of the bacteria
Salmonella typhimurium , Escherichia coli , and Photobacterium phosphoreum (Mutatox assay) (Stott
et al., 1981; Haworth et al., 1983; Nestmann et al., 1984; Khudoley et al., 1987; Kwan et al., 1990;
Hellmer and Bolcsfoldi, 1992; Morita and Hayashi, 1998). Negative results were also indicated for the
induction of aneuploidy * in yeast ( Saccharomyces cerevisiae ) (Zimmermann et al., 1985) and the sex-
linked recessive lethal test in Drosophila melanogaster (Yoon et al., 1985); however, positive results
were reported for meiotic nondisjunction † in Drosophila (Munoz and Barnett, 2002).
1,4-Dioxane was also reported as negative in the mouse lymphoma cell mutagenicity assay
(McGregor et al., 1991; Morita and Hayashi, 1998). In rat hepatocytes, 1,4-dioxane exposure caused
single-strand breaks in DNA at toxic concentrations in vitro (Sina et al., 1983). DNA single-strand
breaks were also demonstrated in hepatocytes following gavage exposure to female rats (Kitchin and
Brown, 1990). 1,4-Dioxane did not affect in vivo DNA repair in hepatocytes or the nasal cavity (Stott
et al., 1981; Goldsworthy et al., 1991), but did increase hepatocyte DNA synthesis indicative of cell
proliferation in several studies (Stott et al., 1981; Goldsworthy et al., 1991; Uno et al., 1994; Miyagawa
et al., 1999). 1,4-Dioxane caused a transient inhibition of ribonucleic acid (RNA) polymerase A and
B in the rat liver (Kurl et al., 1981). Intravenous administration of 1,4-dioxane at doses of 10 or
100 mg/rat produced inhibition of both polymerase enzymes; a quicker and more complete recovery
of activity was noted for RNA polymerase A. 1,4-Dioxane did not covalently bind to DNA under in
vitro study conditions (Woo et al., 1977a). DNA alkylation ‡ was also not detected in the liver 4 h
following a single gavage exposure (1000 mg/kg) in male Sprague Dawley rats (Stott et al., 1981).
1,4-Dioxane did not produce chromosomal aberrations or micronucleus formation in Chinese
hamster ovary (CHO) cells (Galloway et al., 1987; Morita and Hayashi, 1998). Results were negative
in one assay for sister chromatid exchange in CHO cells (Morita and Hayashi, 1998) and were
weakly positive in the absence of metabolic activation in another (Galloway et al., 1987). Studies of
micronucleus formation following in vivo exposure to 1,4-dioxane produced equivocal results.
Negative i ndings were reported for bone marrow micronucleus formation in B6C3F 1 , BALB/c,
CBA, and C57BL6 mice (McFee et al., 1994; Mirkova, 1994; Tinwell and Ashby, 1994). Negative
i ndings were also indicated for micronucleus formation in peripheral blood of CD-1 mice (Morita,
1994; Morita and Hayashi, 1998). Mirkova (1994) reported an increase in bone marrow micronucleus
* Aneuploidy is the condition in which the chromosome number of a cell is not an integer multiple of the normal basic
(haploid) number.
† Nondisjunction is the failure of the chromosomes to properly segregate during meiosis or mitosis, resulting in daughter
cells with abnormal numbers of chromosomes.
‡ DNA alkylation involves the substitution of an alkyl group for hydrogen in DNA that can prevent cell replication by
preventing the separation of two DNA chains during cell division.