The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 236

concentration that corresponds to the concentration producing a 30% decrease in the maximal
response to an electrically evoked seizure. The isoeffective air concentrations for 1,4-dioxane were
approximately 1860 ppm in rats and 2400 ppm in mice. Goldberg et al. (1964) evaluated the effect
of solvent inhalation on pole-climb performance in rats. Female rats were exposed to 0, 1500, 3000,
or 6000 ppm of 1,4-dioxane in air for 4 h per day, i ve days per week, for 10 exposure days. 1,4-
Dioxane exposure produced a dose-related effect on conditioned avoidance behavior in female rats,
while escape behavior was generally not affected. Kanada et al. (1994) evaluated the effect of oral
exposure to 1,4-dioxane on the regional neurochemistry of the rat brain. 1,4-Dioxane was adminis-
tered by gavage to male Sprague Dawley rats at a dose of 1050 mg/kg, approximately equal to one-
fourth the oral LD 50 . 1,4-Dioxane exposure was shown to reduce the content of the neurotransmitters
dopamine and serotonin * in the hypothalamus, while the neurochemical proi le of all other brain
regions in exposed rats was similar to control rats.
Severe liver and kidney degeneration and necrosis were often seen in acute studies [de Navasquez,
1935; Schrenk and Yant, 1936; Kesten et al., 1939; Laug et al., 1939; David, 1964; Japan Bioassay
Research Center (JBRC), 1998a]. JBRC (1998a) additionally reported microscopic changes (histo-
pathological lesions) in the nasal cavity and the brain of rats following two weeks of exposure to
1,4-dioxane in the drinking water.

5.3.2 S UBCHRONIC AND C HRONIC T OXICITY S TUDIES
Subchronic and chronic toxicity studies are conducted in laboratory animals to identify potential
health effects associated with long-term exposure. Well-conducted animal studies use multiple dose
groups with a sufi cient number of animals per group. Multiple parameters are evaluated to assess
toxicological effects (i.e., survival, body weight, food and water consumption, observation of clini-
cal signs, hematology, clinical chemistry, urinalysis, organ weights, gross pathology, and micro-
scopic histopathology). Dose levels that cause signii cant mortality or large decreases in animal
body weight (

10%) are considered to exceed a maximum tolerated dose (MTD). Because animals
at these dose levels are severely ill and may die early (i.e., before the end of the study), useful infor-
mation pertaining to more subtle organ-system changes that may occur at lower doses given over a
longer period of time cannot be obtained. Generally, studies attempt to have the highest-dose group
represent an MTD and include several lower-dose groups to assess other adverse health effects.
Measured parameters from toxicology studies are taken together to determine the nature and sever-
ity of an adverse outcome. For example, changes in hematology, clinical chemistry, and urinalysis
measures can support observed histopathological i ndings of organ-system toxicity. However, small
changes in single measures of these parameters (e.g., less than twofold change in serum enzymes) in
the absence of other measures of toxicity are not always indicative of an adverse health effect.
Histopathological changes are generally considered to be evidence of organ-system toxicity; how-
ever, some microscopic changes may simply represent an adaptive response to chemical exposure.
The study summaries provided here give a brief overview of methods and i ndings. More detailed
information on methodology and statistical analysis of the results can be found in the cited study
reports or publications. Dose levels—stated on the basis of milligrams of 1,4-dioxane per kilogram
of body weight per day—were estimated for the purpose of this summary by using assumptions
regarding animal body weight and drinking-water ingestion (USEPA, 1988), if not provided by the
study authors. Most of the subchronic and chronic studies conducted for 1,4-dioxane were oral
drinking-water studies. Table 5.3 summarizes study details (i.e., species, doses, and duration) for the
oral subchronic and chronic studies for 1,4-dioxane. The highest-dose (or highest-exposure) level
that produced no observed adverse effect (NOAEL) and the lowest-dose level that produced an
observed adverse effect (LOAEL) are indicated, and the toxicological effects that were observed at

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* Dopamine and serotonin are neurotransmitters involved in the regulation of motor function and emotional well-being.