The Toxicology of 1,4-Dioxane - Environmental Investigation and Remediation - page 230

kinetic constants for HEAA formation in rats and humans in order to estimate the dose delivered to
the liver. New experimental data have recently been generated to reduce the uncertainty associated
with the PBPK models for 1,4-dioxane (Sweeney et al., 2008). An updated PBPK model was devel-
oped that may be used in future risk assessments for 1,4-dioxane (Sweeney et al., 2008).

5.2 TOXICITY STUDIES IN HUMANS
The human data for 1,4-dioxane consist of case reports of occupational poisoning, volunteer studies
of acute inhalation exposure, and epidemiology studies of workers occupationally exposed to 1,4-
dioxane. The study details for each of the human studies are presented in Table 5.1 . Several fatal
cases of acute or chronic inl ammation of the kidney (hemorrhagic nephritis) and localized liver
tissue death (centrilobular necrosis of the liver) were related to occupational exposure (i.e., inhala-
tion and dermal contact) to 1,4-dioxane (Barber, 1934; Johnstone, 1959). Neurological changes were
also reported in one case, including headache, elevation in blood pressure, agitation and restless-
ness, and coma (Johnstone, 1959). Perivascular widening (enlargement of blood vessels) was
observed in the brain of this worker, with localized damage to the nerve sheath (demyelination) in
several regions (e.g., cortex and basal nuclei).
Human volunteer studies showed that acute inhalation exposure to high concentrations of 1,4-
dioxane ( 200 ppm) for several minutes produced irritation of the eyes, nose, and throat (Yant et al.,

1930; Fairley et al., 1934; Wirth and Klimmer, 1936; Silverman et al., 1946). Eye irritation was also
seen following a 6-h exposure to 50 ppm 1,4-dioxane (Young et al., 1977). No clinical symptoms or
change in blink frequency, nasal swelling, pulmonary function, or inl ammatory markers in the
plasma (i.e., C-reactive protein, interleukin-6) were seen after exposure to 20 ppm 1,4-dioxane
for 2 h (Ernstgård et al., 2006). The epidemiology studies in occupational workers exposed to 1,4-
dioxane are predominantly negative (Thiess et al., 1976; Bufl er et al., 1978); however, only limited
conclusions can be drawn from these negative i ndings because of the small size of the worker popu-
lations that were studied and the small number of cases available for identii cation of low-level
excess health risk. In addition, the mean exposure duration of the mortality study (Bufl er et al.,
1978) was only i ve years (less than two years for 43% of workers), and the latency period for evalu-
ation was short (less than 10 years for 59% of workers).

>

5.3 TOXICOLOGY STUDIES IN LABORATORY ANIMALS

5.3.1 A CUTE AND S HORT -T ERM T OXICITY S TUDIES ( 1 M ONTH E XPOSURE )

The acute and short-term toxicity studies of 1,4-dioxane in laboratory animals are summarized in
Table 5.2 . Several exposure routes were employed in these studies, including dermal application,
drinking-water exposure, gavage, vapor inhalation, and i.v. or i.p. injection. Mortality was observed
in many acute high-dose studies, and LD 50 values * for 1,4-dioxane were calculated for rats, mice,
and guinea pigs (see Table 5.2; Laug et al., 1939; Smyth et al., 1941; Pozzani et al., 1959). Clinical
signs of central nervous system (CNS) depression were observed, including staggered gait, narcosis, †
paralysis, coma, and death (de Navasquez, 1935; Knoefel, 1935; Schrenk and Yant, 1936; Laug et al.,
1939; Nelson, 1951). The acute neurotoxicity of 1,4-dioxane was further investigated in several studies
(Goldberg et al., 1964; Frantik et al., 1994; Kanada et al., 1994). Frantik et al. (1994) measured the
inhibition of the propagation and maintenance of an electrically evoked seizure discharge following
acute inhalation exposure to 1,4-dioxane. This endpoint has been correlated with the behavioral
effects and narcosis that occur following acute exposure to higher concentrations of organic solvents.
Linear regression analysis of the concentration-effect data was used to calculate an isoeffective air

<

* LD 50 is the median lethal dose of a toxin at which 50% of the exposed organisms are killed.
† Narcosis is a state of stupor, drowsiness, or unconsciousness produced by drugs or toxic substances.