The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 227

5 The Toxicology of 1,4-Dioxane
Julie A. Stickney

The risk assessment and regulation of 1,4-dioxane as an environmental contaminant depend on
assumptions regarding human exposure and toxic potency. The toxicity of 1,4-dioxane in humans is
evaluated by considering studies in laboratory animals and limited data from human exposures.
This chapter briel y summarizes the toxicological data for 1,4-dioxane. The uptake and behavior of
this chemical within the body are discussed (i.e., toxicokinetics). Toxicity studies in humans are
presented; these consist of case reports of occupational poisoning, volunteer studies of acute inhala-
tion exposure, and limited epidemiology studies of occupational workers. The acute effects of high-
dose exposures (less than one month in duration) on laboratory animals are also described. These
studies are relevant in identifying the potential outcomes of accidental or industrial poisoning from
1,4-dioxane, but do not provide useful information about lower-level environmental exposures.
Subchronic and chronic laboratory animal studies are designed to evaluate the potential for health
effects to result from exposure to different doses over longer periods of time. These studies are
generally used to assess long-term environmental exposures when human data are limited or absent.
Brief study summaries are provided for the subchronic and chronic toxicity studies conducted for
1,4-dioxane. Also discussed are mechanistic studies that provide some insight into the potential
mechanisms of action leading to toxicological outcomes.
Taken together, the human and laboratory animal data identify possible health effects that may
result from exposure to 1,4-dioxane. The primary exposure routes leading to 1,4-dioxane toxicity
are inhalation and ingestion. Signii cant inhalation exposures to 1,4-dioxane are likely to occur only
in occupational settings. Oral exposure in humans may result from ingestion of contaminated drink-
ing water. Liver and kidney toxicities are the primary noncancer health effects associated with
exposure to 1,4-dioxane in humans and laboratory animals. Liver tumors found in rats and mice in
several lifetime drinking-water studies suggest that oral exposure to 1,4-dioxane may result in car-
cinogenicity in humans. Liver tumors generally occur at dose levels that also produce liver toxicity.
Genotoxicity data for 1,4-dioxane are generally negative and do not support a mutagenic mode of
action for carcinogenicity. Alternative modes of carcinogenic action may involve cytotoxicity fol-
lowed by regenerative cell proliferation or growth promotion of liver cells in the absence of signii -
cant cytotoxicity (i.e., mitogenesis).

5.1 TOXICOKINETICS
Toxicokinetics describe the absorption, distribution, metabolism, and excretion of a substance from
the human body following exposure by oral, dermal, or inhalation routes. The toxicokinetics of 1,4-
dioxane are described by using human volunteer studies, laboratory animal studies, in vitro test
systems, and computer modeling [i.e., physiologically based pharmacokinetic (PBPK) models].
Toxicokinetic data for 1,4-dioxane in humans are limited; however, the absorption, distribution,
metabolism, and elimination of this compound are well described in rats exposed via the oral, inha-
lation, and intravenous (i.v.) routes.
1,4-Dioxane is well absorbed following oral and inhalation exposure. Studies in workers and
human volunteers demonstrated rapid absorption following inhalation exposure to 1,4-dioxane by
measuring concentrations of 1,4-dioxane and its metabolite, β -hydroxyethoxy acetic acid (HEAA),

229