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evidence for an association between cancer mortality and exposure to plutonium.
Plutonium dose-
response relationships for lung cancer mortality have been corroborated in four Mayak studies (Gilbert et
al. 2004; Jacob et al. 2005; Kreisheimer et al. 2003; Sokolnikov et al. 2008). Studies of U.K. and U.S.
facilities have examined cohorts of workers who had substantially lower estimated plutonium exposures
and corresponding internal radiation doses than the Mayak cohorts. Collectively, findings from these
studies are not as consistent as
the Mayak studies, although significantly higher incidence of cancer
mortality in certain groups of plutonium workers has been found in some studies, higher cancer incidence
and/or risks for tissues that received the highest plutonium radiation doses (i.e., lung, liver, bone) have not
been found, making causal connections of these outcomes to plutonium exposure more uncertain (Brown
et al. 2004; Carpenter et al. 1998; McGeoghegan et al. 2003; Omar et al. 1999; Wing et al. 2004).
Uncertainties in exposures received by each of these populations are a major contributor to the overall
uncertainty in estimates of radiation doses and dose-response relationships. For the Mayak cohort, an
extensive collaborative effort between U.S. and Russian scientists has led to many improvements in both
external and internal doses. The improved doses (Leggett et al. 2005) have not been
used in published
analyses, but are likely to be used future analyses (Leggett et al. 2005; Vasilenko et al. 2007). Continued
follow up of these cohorts, using improved exposure estimates, would extend
our understanding of dose-
response relationships. Examination of these cohorts for end points other than cancer may extend our
understanding of dose-response relationships for effects that have been consistently observed in animals
(e.g., lymphopenia and neutropenia and potential secondary consequences of these effects on the immune
system). Continued epidemiological studies should receive high priority.
Biomarkers of Exposure and Effect.
Exposure.
Biomarkers of exposure to plutonium are well established. Plutonium-specific radioactivity
from internalized plutonium can be detected by external radiation detection devices. Plutonium can also
be detected in the blood, urine, feces, and tissue samples from individuals who have internalized
plutonium deposits. Estimates of the extent of exposure can be made using PBBK models. Additional
studies designed to assess biomarkers of exposure to plutonium are not necessary.
Effect.
Biomarkers of effect resulting from plutonium-released radiation are not specific to plutonium.
Radiological effects in animals exposed to plutonium have been well documented.
Additional studies of
biomarkers of effect for plutonium are not necessary.
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Absorption, Distribution, Metabolism, and Excretion.
For laboratory animals, detailed
quantitative information is available regarding the absorption, distribution, and excretion of plutonium
compounds following acute exposure by inhalation or injection. There is no information on the
toxicokinetics of plutonium following chronic exposure to low levels, and studies in this area would be
more applicable to human exposure situations than single exposure studies.
Information concerning the
toxicokinetics of plutonium in adult animals following oral exposure is available. However, previous
animal studies have indicated that very little plutonium is absorbed following oral exposure. Therefore,
studies of kinetics following oral exposure are not needed at this time. Additional studies of age-related
differences in the toxicokinetics of plutonium would be useful. Little is known regarding the absorption,
distribution, and excretion of plutonium compounds following dermal exposure. However,
it appears that
the skin is an effective barrier against most plutonium compounds.
Comparative Toxicokinetics.
Numerous studies of the distribution of plutonium in humans (i.e.,
autopsy studies of individuals occupationally exposed to plutonium) have shown that the general pattern
of distribution of plutonium in humans is consistent with that observed in various animal models, with the
highest portion of the body burden in lung (following inhalation exposures), skeletal tissues, and liver.
Epidemiologic studies of health outcomes among workers in industries that produce and/or process
plutonium have provided evidence for increased risk of lung, liver, and bone cancers in
association with
exposures to plutonium. These observations are consistent with the pattern of health effects observed in
animals, particularly dogs. Additional comparative toxicokinetics studies do not appear necessary at this
time.
Methods for Reducing Toxic Effects.
Current strategies for reducing toxic effects of plutonium
are to hasten the elimination of plutonium from the body by administering complexing/chelating agents.
A major challenge in applying this strategy is that Pu(IV) in the body forms insoluble precipitates within
tissues which are unavailable for interaction with dissolved substances. Most agents that have been tested
perform relatively poorly at mobilizing plutonium from bone, which harbors a large fraction of the body
burden. Continued research to develop more effective agents that have low toxicity would potentially
lead to more successful therapies for reducing toxic effects of plutonium.
This research should receive
high priority.
Children’s Susceptibility.
Data needs relating to both prenatal and childhood exposures, and
developmental effects expressed either prenatally or during childhood, are discussed in detail in the
Developmental Toxicity subsection above.