51
PLUTONIUM
3. HEALTH EFFECTS
Exposure of Dogs to
239
PuO
2
.
Centrilobular congestion and vacuolization were observed in dogs that
inhaled
239
PuO
2
(initial lung burden ≥1 kBq/kg), although no consistent changes in serum liver enzymes
were seen (DOE 1988a).
Exposure of Dogs to
239
Pu(NO
3
)
4
.
Serum liver enzymes ALP and glutamic pyruvic transaminase (GPT)
were significantly elevated In PNL dogs that inhaled
239
Pu(NO
3
)
4
, at levels resulting in initial lung
burdens ≥0.19 kBq/kg (DOE 1988b, 1994a; Park et al. 1995). Bile duct hyperplasia was reported in
controls and plutonium-exposed dogs and did not appear to exhibit dose-related increased incidence or
severity (Dagle et al. 1996). However, the severity of observed nodular hyperplasia was significantly
higher in dogs with mean initial lung burdens ranging from 0.028 to 1.02 kBq/kg (Dagle et al. 1996).
Exposure of Other Laboratory Animal Species.
Degenerative liver lesions (hepatic degeneration,
necrosis, fibrosis, and amyloidosis) were reported in Syrian hamsters exposed to
239
PuO
2
(once or
repeatedly every other month for a total of seven doses over 12 months) at a target
239
Pu lung burden of
1.8 kBq/hamster; it was noted that the lesions observed in these hamsters were typical of those usually
seen in aged Syrian hamsters (Lundgren et al. 1983).
The highest NOAEL values and all reliable LOAEL values for hepatic effects in each species and
duration category are recorded in Table 3-3.
The highest NOAEL values and all reliable LOAEL values for hepatic effects in dogs and nonhuman
primates exposed to aerosols of plutonium are recorded in Table 3-3 and plotted in Figure 3-1.
Renal Effects.
Possible associations between exposure to plutonium and mortality from diseases of
the kidney and genitourinary tract have been examined in studies of workers at plutonium production
and/or processing facilities in the United States (Rocky Flats) (Wiggs et al. 1994) and the United
Kingdom (Sellafield) (McGeoghegan et al. 2003; Omar et al. 1999). These studies are summarized in
Table 3-2 and study outcomes for mortality are described in Section 3.2.1.1. Collectively, these studies
have not found significant associations between mortality rates from kidney or genitourinary tract disease
and exposure to plutonium among workers at these facilities.
52
PLUTONIUM
3. HEALTH EFFECTS
Endocrine Effects.
Epidemiological Studies in Humans.
Possible associations between exposure to plutonium and mortality
from endocrine disorders have been examined in studies of workers at plutonium production and/or
processing facilities in the United Kingdom (Sellafield) (McGeoghegan et al. 2003; Omar et al. 1999).
These studies are summarized in Table 3-2 and study outcomes for mortality are described in
Section 3.2.1.1. Collectively, these studies have not found significant associations between mortality
rates from endocrine disorders and exposures to plutonium among workers at these facilities.
Studies in Animals.
Hypoadrenocorticism was reported in
238
PuO
2
-exposed PNL dogs (n=6) with
individual initial lung burdens in the range of 1–25 kBq/kg body weight and was considered the cause of
death in 3 of the 6 dogs (Park et al. 1997). The time to detection of hypoadrenocorticism ranged from
1,263 to 4,616 days after exposure; physical symptoms included depression, weakness, dehydration,
bradycardia, and anorexia. Laboratory findings in affected animals (hemoconcentration, altered serum
Na:K ratio, hypochloremia, hypoglycemia, metabolic acidosis, and hypercalcemia) were consistent with
adrenal cortical insufficiency. Cardiovascular changes (bradycardia and other cardiac arrhythmias) were
consistent with hypoadrenocorticism-induced hypokalemia. Histopathological findings included bilateral
adrenal cortex atrophy with capsular thickening and fibrosis, and mononuclear cell infiltration. Results of
ACTH response tests indicated that hypoadrenocorticism resulted from adrenal cortical insufficiency
rather than from altered pituitary function. Based on the presence of anti-adrenal antibodies in serum,
hypoadrenocorticism may have resulted from an autoimmune disorder caused by radiation damage to the
lymphatic system (Park et al. 1997).
3.2.1.3 Immunological and Lymphoreticular Effects
Epidemiological Studies in Humans.
Possible associations between exposure to plutonium and mortality
from immunological or lymphoreticular diseases have been examined in studies of workers at plutonium
production and/or processing facilities in the United States (Rocky Flats) (Wiggs et al. 1994) and the
United Kingdom (Sellafield) (McGeoghegan et al. 2003; Omar et al. 1999). These studies are
summarized in Table 3-2 and study outcomes for mortality are described in Section 3.2.1.1. Collectively,
these studies have not found statistically significant associations between mortality rates from diseases of
the immunological or lymphoreticular systems and exposures to plutonium among workers at these
facilities.
53
PLUTONIUM
3. HEALTH EFFECTS
Studies in Animals.
As discussed in detail in Section 3.4, Toxicokinetics, inhaled plutonium compounds
are translocated to tracheobronchial lymph nodes, resulting in a high tissue concentration of plutonium
and sclerotic atrophy of lymph nodes. Exposure of lymphocytes in plutonium-laden tracheobronchial
lymph nodes is considered the probable cause of lymphopenia in the plutonium-exposed dogs (Ragan et
al. 1976). Effects of inhaled plutonium on the number lymphocytes circulating in blood are reviewed in
Section 3.2.1.2, Hematological Effects.
Histopathologic lesions of lymph nodes, particularly tracheobronchial lymph nodes, have been observed
following exposure to
238
PuO
2
,
239
PuO
2
, or
239
Pu(NO
3
)
4
. Fibrosis and loss of lung-associated and
mediastinal lymph nodes were observed in the
238
PuO
2
-exposed ITRI dogs with the highest initial lung
burdens, although specific levels resulting in this effect were not specified (Muggenburg et al. 1996).
Severity of non-neoplastic lesions in
238
PuO
2
-exposed PNL dogs was related to dose, progressing from
lymphoid atrophy of medullary cords at an initial lung burden of 0.061 kBq/kg to significant lymph node
atrophy with hypocellular scar tissue replacing lymphoid tissue at higher (not otherwise specified) initial
lung burdens (Park et al. 1997). Similar dose-related atrophy and fibrosis of lung-associated, mediastinal,
sternal, and hepatic lymph nodes were observed in dogs exposed to
239
PuO
2
(DOE 1988a; Muggenburg et
al. 1999, 2008). Sclerotic lymph nodes were observed in the groups of
239
Pu(NO
3
)
4
-exposed PNL dogs
with mean initial lung burdens ≥5.9 kBq/kg, but lymph node lesions in these dogs were considered less
severe than those observed in
238
PuO
s
- or
239
PuO
2
-exposed dogs (DOE 1986b, 1989).
Results of studies on immunological function indicate that inhalation exposure to
239
PuO
2
impairs T-cell
response to antigens, as indicated by decreased response to antigen (DOE 1978a). Davila et al. (1992)
detected accelerated aging of the T-cell response to mitogenic stimulation in dogs that had been exposed
to
239
PuO
2
10 years earlier at levels resulting in mean initial lung burdens ≥6.5 kBq (0.61 kBq/kg,
assuming a body weight of 10.7 kg at time of
239
PuO
2
aerosol exposure). Other reports of
239
PuO
2
-
induced effects from plutonium exposure include decreases in pulmonary alveolar macrophages in mice
(Moores et al. 1986) and depressed antibody-forming cells in hamsters (Bice et al. 1979).
The highest NOAEL values and all reliable LOAEL values for immunological and lymphoreticular
effects in each species and duration category are recorded in Table 3-3.
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