43
PLUTONIUM
3. HEALTH EFFECTS
associations between mortality rates from noncancer respiratory tract diseases
and exposure to plutonium
among workers at these facilities.
Possible associations between exposure to plutonium and pulmonary fibrosis was examined in a cohort of
workers (n=326) at Rocky Flats (Newman et al. 2005). The study assessed lung interstitial abnormalities
from the most recent available x-rays in relation to estimated lung equivalent doses from plutonium.
Estimated lung equivalent doses ranged from 0 to 28 Sv (approximately 73% <1 Sv). The odds ratio
(OR) (adjusted for age, smoking status, and evidence from pleural abnormalities from possible asbestos
exposure) was significant for the dose group with lung equivalent doses ≥10 Sv (OR 5.3, 95% CI: 1.2–
23.4). The report of Newman et al. (2005) was based on scoring radiographs for the severity of chest
abnormalities consistent with fibrosis, and did not include information regarding a possible association
between these lung abnormalities and clinical symptoms of disease.
Studies in Animals.
Radiation pneumonitis has been observed following plutonium (primarily insoluble)
aerosol exposure of dogs, nonhuman primates (monkeys and baboons), and rodents.
As discussed in
Section 3.2.1.1, radiation pneumonitis was identified as primary, major contributing, or incidental cause
of death in some dogs and nonhuman primates that inhaled
238
PuO
2
,
239
PuO
2
, or
239
Pu(NO
3
)
4
aerosols.
Muggenburg et al. (2008) studied the effect of plutonium ILB and radiation dose on radiation
pneumonitis in beagles as part of a plutonium lifespan composite study.
The relationship between
pneumonitis induction and the cause of death was reported to be a function of the plutonium ILB, the
resulting cumulative radiation dose, and the particle size to some extent. Increased ILB and plutonium
dose rate were associated with the fraction of animals with radiation pneumonitis as primary, major
contributing, or incidental cause of death. A trend was observed for the induction of radiation
pneumonitis at lower ILBs in the 0.75 and 1.5 µm AMAD groups than in the 3 µm AMAD group. At
radiation doses sufficient to produce radiation pneumonitis, the resulting inflammation was
a chronic
symptom due to long-term retention of
239
PuO
2
in the lung. As a result,
239
PuO
2
-induced radiation
pneumonitis was always associated with pulmonary fibrosis. The radiation pneumonitis/pulmonary
fibrosis progressively impaired lung function, including alveolar-capillary gas exchange, resulting in
increases
in respiratory rate, minute volume, arterial CO
2
pressure, and lung stiffness, along with
decreases in tidal volume and arterial O
2
pressure. Symptoms in order of decreasing frequency were
tachypnea, increased breath sounds, body weight loss, anorexia, dyspnea, cyanosis, bradycardia, and
discharge from the nose, eyes, or mouth. Increasing radiation dose and
dose rate corresponded to
44
PLUTONIUM
3. HEALTH EFFECTS
progressively shorter times to onset of symptoms and increased severity of effects (Muggenburg et al.
2008).
Results of inhalation toxicity studies in dogs show that the clinical course of radiation pneumonitis is
similar following exposure to
238
PuO
2
or
239
PuO
2
. The typical initial presenting symptom of radiation
pneumonitis is tachypnea (increased number of breaths per minute) with radiological evidence of
pulmonary interstitial infiltrate. Histopathological findings include interstitial pneumonia with alveolar
epithelial hyperplasia, vasculitis, inflammatory cells infiltration, and pulmonary fibrosis (Muggenburg et
al. 1996, 1999, 2008; Park et al. 1997). Results of the ITRI and PNL studies indicate that radiation
pneumonitis in the
239
PuO
2
-exposed dogs occurred at lower initial lung burdens and had a shorter time to
onset of symptoms (Muggenburg et al. 2008) compared to that observed in
238
PuO
2
- or
239
Pu(NO
3
)
4
-
exposed dogs. This observation is consistent with toxicokinetic differences observed for inhaled
plutonium compounds,
showing that inhaled
239
PuO
2
is cleared from the lung more slowly than
238
PuO
2
and
239
Pu(NO
3
)
4
(see Section 3.4, Toxicokinetics).
Exposure of Dogs to
238
PuO
2
.
In the ITRI
238
PuO
2
dog studies, the first symptom of radiation
pneumonitis (tachypnea) was observed at approximately 600 days after initial exposure (Muggenburg et
al. 1996). Pulmonary function tests performed periodically over several years on a subgroup of dogs with
radiation pneumonitis (mean initial lung burden 28 kBq/kg) showed progressive changes in lung function
including decreased dynamic lung compliance, decreased CO diffusing capacity, increased alveolar-
arterial pO
2
, pulmonary edema (a near terminal event), and decreased arterial pO
2
(terminal event).
Pulmonary interstitial or septal fibrosis was observed at necropsy in all dogs with radiation pneumonitis;
severity was dose-related. Radiation pneumonitis was the primary cause of death
in eight dogs with
initial lung burdens of 8.3–45 kBq/kg (Muggenburg et al. 1996). Similar observations were reported in
the PNL studies on
238
PuO
2
, with chronic radiation pneumonitis observed in dogs with initial lung
burdens ≥0.28 kBq/kg (Park et al. 1997).
Exposure of Dogs to
239
PuO
2
.
Chronic radiation pneumonitis also was observed in the ITRI and PNL
dogs exposed to
239
PuO
2
aerosols. In the ITRI studies, tachypnea was first observed in cases of nonfatal
radiation pneumonitis approximately 1 year after exposure (Muggenburg et al. 1988).
Morphological
changes to the lung included alveolar epithelial hyperplasia and interstitial fibrosis (Muggenburg et al.
2008). Radiation pneumonitis was observed in dogs dying from 0.3 to 11.7 years after inhaling
239
PuO
2
,
with the time to death inversely related to initial lung burden (Hahn et al. 1999; Muggenburg et al. 1999,
2008). The lowest initial lung burden causing fatal radiation pneumonitis was 1.0 kBq/kg (Muggenburg