23
PLUTONIUM
3. HEALTH EFFECTS
(e.g., relatively low mortality or morbidity rates in workers because of loss of unhealthy workers from the
working population), false positive findings attributable to assessments of multiple
outcomes in a single
study, and adequate treatment of confounding and co-variables that may affect the measured outcome
independently or in association with plutonium radiation dose.
Numerous animal studies are available regarding adverse health effects following inhalation exposure to
plutonium compounds; studies were conducted in nonhuman primates, dogs, and rodents. The discussion
of animal studies in this profile has primarily focused on the wealth of information that has developed on
the toxicology of plutonium in beagle dogs exposed by inhalation. The series of lifetime dog studies,
conducted by the Inhalation Toxicology Research Institute (ITRI) and Battelle Pacific Northwest
Laboratory (PNL) as a multi-laboratory effort during the 1950s through the 1990s, provide the most
complete evaluations of the adverse health effects associated with inhaled plutonium compounds. Dogs
were selected as the experimental model for these studies based on their relatively long life span (12–
15 years) and physiologic and anatomical features common to dogs and humans (particularly regarding
hematopoietic,
pulmonary, and skeletal systems) (DOE 1989). Although conducted by two different
laboratories, the ITRI and PNL studies used similar experimental protocols and evaluated the same
comprehensive toxicological end points, providing an extensive database on the toxicity of inhaled
plutonium. Therefore, information provided in the following sections primarily relies on data from the
lifetime exposure studies in the ITRI and PNL dogs; results of inhalation studies conducted in rodents and
nonhuman primates are briefly reviewed and included as supportive data.
The most widely studied
plutonium compound,
239
PuO
2
, is only moderately soluble, which results in long-
term retention in the lung following inhalation exposure. Other plutonium compounds assessed in
lifetime dog studies include
238
PuO
2
(more rapidly cleared from the lung than
239
PuO
2
due to much higher
specific activity, which results in fragmentation) and
239
Pu(NO
3
)
4
(more chemically soluble than
239
PuO
2
).
Studies conducted by PNL investigated the effects of single inhalation exposures of adult dogs to
238
PuO
2
,
239
PuO
2
, or
239
Pu(NO
3
)
4
. The lifetime exposure studies conducted by ITRI evaluated the effects of single
exposures of adult dogs to
238
PuO
2
and
239
PuO
2
of varying particle sizes, single
exposures of juvenile and
elderly dogs to
239
PuO
2
, and repeated exposures of adult dogs to
239
PuO
2
(Table 3-1). An overview of the
complete series of lifetime exposure studies conducted by both PNL and ITRI was published by DOE
(1989). A substantial amount of health effects data for the Pu-exposed dogs is available. In addition,
comprehensive reports were published in the late 1990s for
238
PuO
2
-induced health effects in the ITRI
(Muggenburg et al. 1996) and PNL (Park et al. 1997) dogs. A comprehensive report has recently been
finalized for
239
PuO
2
-exposed dogs from the ITRI facility (Muggenburg et al. 2008).
At present, available
24
PLUTONIUM
3. HEALTH EFFECTS
Table 3-1. Selected Exposure Details from the ITRI and PNL Dog Studies and
Conversion Procedures Used to Compare Initial Lung Burden in Common
Units of kBq/kg Body Weight
Exposure and conversion information
Study references
238
PuO
2
:
ITRI evaluated single inhalation exposure of young
adult male and female
dogs (12–15 months of age) at two AMAD particle sizes, 1.6 and 2.9 µm.
Test material was prepared at high calcining temperatures (700
C).
Exposed dogs were assigned to one of six groups, which resulted in
median ILBs (range) of 0 (0), 0.36 (0.10–0.69), 1.05 (0.77–1.55),
2.84 (1.85–4.06), 5.99 (4.42–8.42), 11.2 (8.59–15.2), and 23.7 (15.3–45.4)
kBq/kg body weight for dogs inhaling 1.6 µm AMAD particles, and 0 (0),
0.47 (0.15–0.77), 1.35 (0.84–1.70), 3.00 (2.39–3.79), 7.02 (4.07–9.37),
12.6 (10.4–15.6), and 25.4 (19.7–43.1) kBq/kg/body weight for dogs
inhaling 2.9 µm AMAD particles. Because effects did not appear to depend
on particle size, the study authors combined the results from the separate
studies.
PNL evaluated single inhalation exposure of young adult male and female
dogs (12–20 months of age). Test material prepared
at high calcining
temperatures (750
C). Mean ILBs of 0, 0.13, 0.68, 3.1, 13, 52, and
210 kBq were reported for controls and 6 experimental groups (Park et al.
1997), and were converted to mean ILBs of 0, 0.01, 0.061, 0.28, 1.17, 4.68,
and 18.9 kBq/kg body weight by dividing the reported ILBs by the reported
median body weight of 11.1 kg at aerosol exposure.
239
PuO
2
:
ITRI evaluated single inhalation exposure of young adult male and female
dogs (12–15 months of age) at three different AMAD particle sizes, 0.75,
1.5, and 3.0 µm. Test material was prepared at high calcining
temperatures (700
C). Because effects did not appear to depend on
particle size, the study authors combined the results. Median ILBs (range)
of 0 (0), 0.19 (0.026–0.35), 0.63 (0.37–0.96), 1.6 (1.0–2.4), 3.7 (2.6–4.8),
6.3 (5.2–9.3), 14 (10–20), and 30 (21–74) kBq/kg
body weight were
reported for controls and six experimental groups.
PNL evaluated single inhalation exposure of young adult male and female
dogs (12–20 months of age) at an AMAD particle size of 2.3 µm. The test
material was prepared at high calcining temperatures (750
C). Mean ILBs
of 0, 0.12, 0.69, 2.7, 11, 41, and 213 kBq were reported for controls and
six experimental groups, and were converted to mean ILBs of 0, 0.01,
0.064, 0.25, 1.0, 3.83, 19.9 kBq/kg body weight by dividing the reported
ILBs by the reported mean body weight of 10.7 kg at the time of aerosol
exposure.
ITRI evaluated single and repeated exposure of young adult male and female
dogs (12–15 months of age) at an AMAD particle size of 0.75 µm.
Repeated exposures were once every 6 months for a total of 20 exposures.
A mean ILB of 3.9 kBq/kg was reported
for dogs exposed once; the mean
total alveolar deposition was 5.3 kBq/kg body weight in the repeatedly-
exposed dogs.
DOE 1989; Gillett et
al. 1988; Hahn et al.
1991a; Muggenburg
et al. 1996
DOE 1978a, 1988a,
1989; Park et al.
1995, 1997; Weller et
al. 1995a, 1996
Diel et al. 1992; DOE
1989; Hahn et al.
1999; Muggenburg et
al. 1988, 1999
DOE 1988a, 1989;
Weller et al. 1995b
Diel et al. 1992; DOE
1989