Uranium - Toxicology of Metals - page 870

muscle was investigated in the rat and found to be high-
est in kidney and bone, at times ranging from 12 days to
18 months (Pellmar et al ., 1999).
ICRP (1979) developed a uranium compartmental
model for uranium distribution and excretion, which
Fisher et al . (1991) later adjusted on the basis of expo-
sure events. ICRP (1995) subsequently developed the
current biokinetic model that applies to uranium after
its uptake to blood, regardless of exposure route. It is
patterned after composite human and animal data and
recognition that uranyl and calcium ions have similar
skeletal kinetics. Its features include fi ve major com-
partments (for blood, kidney, liver, skeleton, and soft
tissues) with multiple subcompartments and bidirec-
tional transfer rates for three solubility types.

days for the remainder (ICRP, 1979). More recent esti-
mates of the biological half-times for the compart-
ments are 2 and 50-60 days (Diamond et al ., 1989), 2
and 13 days (Bentley et al ., 1985), or 3 and 103 days
(Wrenn et al ., 1986). The initial half-time for retention
in bone has been estimated to be 11 days. The amount
excreted is expected to be a function of intake route,
because ingested uranium is excreted mainly unab-
sorbed in feces, whereas the absorbed amount (e.g.,
from inhalation or dermal absorption) is excreted pri-
marily through the kidneys. This was observed in an
Italian population compared with one in Germany and
indicated the importance of having appropriate local
reference levels (Bagatti et al ., 2002). Because the rate
of uranium excretion in urine can be used to approxi-
mate the long-term average rate of systemic uptake
(discounting the small retained fraction), the values
in Table 4 can be used as comparators where suitable
local reference levels are unavailable.
Uranium has been shown to transfer to human
breast milk, with a transfer factor of 21.3 (ratio of con-
centrations in food [

5.3 Elimination and Excretion
Most inhaled uranium returns to the throat through
the mucociliary elevator and joins ingested uranium,
and more than 95% of this is excreted unabsorbed in
the feces. Fecal excretion accounted for 99% of the
uranium excreted by uranium ore crushermen who
inhaled ore dust (Fisher et al., 1983).
Uranium remaining in the lung is eliminated on
the basis of solubility. A worker who inhaled uranium
tetrafl uoride for 5 minutes excreted 0.2% of the ura-
nium on day 1, and this gradually increased for 60
days and then returned to normal after approximately
1000 days (Zhao and Zhao, 1990). The long-term half-
time for human lung on the basis of uranium dioxide
exposure of German workers was estimated to be 109
days (Schieferdecker et al ., 1985). In studies of ani-
mals involving more soluble compounds, 60% of the
retained uranium as nitrate (Ballou et al ., 1986), hex-
afl uoride (Leach et al ., 1984), and trioxide (Morrow
et al ., 1982) was excreted in urine within 1 day for the
rat, dog, and guinea pig.
Once uranium reaches the bloodstream, by what-
ever route of exposure, there is an initial rapid excre-
tion in which renal and fecal excretion, respectively.
account for >98% and <2% of the total (Spencer et al .,
1990). Urinary elimination is facilitated by the ultra-
fi ltrable nature of the uranyl-bicarbonate and uranyl-
citrate complexes, which are fi ltered in the glomerulus
and tubules. Tetravalent uranium attached to plasma
protein is less fi lterable and is eliminated over a longer
period of time. Once the uranyl ion is split from its
complex in the kidney, the uranium readily transfers
to urine if the pH is high. At low pH, the excretion can
be delayed.
The pattern of excretion tends to follow a two-phase
model for which the half-times in kidneys have been
reported as 1-6 days for 99% of the uranium and 1500

g/L]), although
signifi cant individual differences were observed (Wap-
pelhorst et al ., 2002). This indicated to the authors that
5% of the oral intake could be excreted in breast milk.
A much smaller value would be anticipated consid-
ering that <0.1-6% of oral intake becomes systemic
(Section 5.1.2), and most of that is excreted in urine.
In animals, uranium has been found to cross the
placenta after parenteral administration.

µ g/kg] to milk [ µ

6 MECHANISMS OF ACTION

The mechanistic theories of uranium toxicity have
been probed primarily by traditional means. They
have looked at temporal changes in urinary levels of
several analytes (e.g., protein, β 2 -microglobulin, amino

acids, alkaline phosphatase, ALT, and glucose) as a
function of uranium intake. But, these are nonspecifi c
indicators of uranium damage that can be caused by
other agents. The database has been supplemented
more recently with genetic tools primarily involving
in vitro exposures of cells as well as in vivo studies after
acute injections or more prolonged exposures through
drinking water or inhalation. The in vitro immersion
and in vivo injection studies can deliver higher concen-
trations of uranium to cells than is possible with tradi-
tional methods or relevant to environmental exposures
(Muller et al ., 2006). This facilitates more robust expres-
sion of subtle effects or observation of effects that may
not occur otherwise after inhalation, oral, or dermal
exposure. These studies have examined mechanisms
of cellular uptake of uranium and toxicity to a number