The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 255

for 1,4-dioxane-induced cell proliferation. Mechanistic studies also provide evidence of cell pro-
liferation, but do not indicate whether mitogenesis or cytotoxicity is responsible for increased cell
turnover (Stott et al., 1981; Goldsworthy et al., 1991; Uno et al., 1994; Miyagawa et al., 1999).
Inhalation of droplets of drinking water may be responsible for the nasal tumors observed in
rats following chronic exposure to 1,4-dioxane in drinking water (Goldsworthy et al., 1991;
Sweeney et al., 2008). In this case, the mode of action may involve chronic irritation followed by
regenerative hyperplasia leading to the formation of nasal tumors. Histopathological lesions in
female rats were suggestive of toxicity and regeneration in this tissue (i.e., atrophy, adhesion,
inl ammation, nuclear enlargement, and hyperplasia and metaplasia of respiratory and olfactory
epithelium) (JBRC, 1998b).
5.6 1,4-DIOXANE TOXICOLOGY AND RISK ASSESSMENT
Environmental risk assessment of 1,4-dioxane involves an understanding of potential human expo-
sures and toxic potency. Drinking-water contamination with this chemical could result in exposure
via ingestion, dermal contact, and inhalation. The limited human and animal data available for the
inhalation route suggest that toxic outcomes occur only at high levels of exposure. Toxicity studies
for the dermal exposure route are lacking, but limited data suggest that dermal penetration may not
be signii cant. Oral exposure is the primary exposure route of concern for 1,4-dioxane, and most of
the laboratory animal studies have used this exposure route.
In characterizing the toxic potency of 1,4-dioxane, human and laboratory animal studies should
both be considered. The most useful studies provide an evaluation of the dose-response relationship
for the toxic endpoints of concern. These data can be used to quantify the toxic potency and provide
a numerical toxicity value for human health risk assessment. Studies of 1,4-dioxane exposure in
humans do not provide adequate information for evaluating possible health effects resulting from
environmental exposure to this chemical. In this case, laboratory animal studies must be relied upon
to provide quantitative toxicity information for use in risk assessment. Data are available to describe
the dose-response relationship for both target organ toxicity (i.e., liver and kidney toxicities) and
cancer. Noncancer health effects are generally evaluated by using a reference dose (RfD) value,
which is dei ned as an estimate (with uncertainty spanning perhaps an order of magnitude) of a
daily oral exposure to the human population (including sensitive subgroups) that is likely to be with-
out an appreciable risk of deleterious effects during a lifetime. An RfD value is not currently avail-
able for 1,4-dioxane on USEPA's Integrated Risk Information System (IRIS) database (USEPA,
2007); however, an RfD value may be developed in the future by using chronic bioassay data for
liver and kidney toxicities (Fairley et al., 1934; Argus et al., 1965, 1973; Kociba et al., 1974; NCI,
1978; JBRC, 1998c).
Oral cancer slope factors (CSFs) or inhalation unit risk values are developed from laboratory
animal studies for use in cancer risk assessment. An oral CSF value of 0.011 (mg/kg-day) -1 previ-
ously published on USEPA's IRIS database (USEPA, 2007) was based on the dose-response data
for nasal cavity carcinomas in male Osborne-Mendel rats (NCI, 1978); the USEPA used the default
methodology of linear low-dose extrapolation. The verii cation date for the IRIS assessment was
February 3, 1988. Since that time, additional cancer bioassay data have become available (JBRC,
1998c), and several studies have been published that shed light on the possible mode of action for
cancer induction in experimental animals (Goldsworthy et al., 1991; Uno et al., 1994; Miyagawa
et al., 1999; Nannelli et al., 2005). PBPK models are also available for 1,4-dioxane that estimate the
internal dose at the target organ (liver) and take into account species differences (i.e., rats vs.
humans) and nonlinear pharmacokinetics (Reitz et al., 1990; Leung and Paustenbach, 1990; Sweeney
et al., 2008).
For chemicals that are considered to be possibly carcinogenic to humans, the cancer risk assess-
ment is an important component of environmental risk assessment and regulation. The CSF repre-
sents the relationship between the dose of a chemical and the incidence of humans or animals with