Radiation Research

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Radiation Research 168(5):582-592. 2007
doi: 10.1667/RR0903.1

Bone Cancer Risk of 239Pu in Humans Derived from Animal Models

Harmen Bijwaard and Fieke Dekkers

RIVM, Laboratory of Radiation Research, Bilthoven, The Netherlands

1Address for correspondence: RIVM-National Institute for Public Health and the Environment, Laboratory for Radiation Research, Antonie van Leeuwenhoeklaan 9, 3721 MA Bilthoven, The Netherlands;

Abstract

Bijwaard, H. and Dekkers, F. Bone Cancer Risk of 239Pu in Humans Derived from Animal Models. Radiat. Res. 168, 582– 592 (2007).

Two-mutation model fits to bone cancer mortality data from mice, rats and beagle dogs injected with 239Pu or 226Ra show that (1) it is possible to fit the radiation-related parameters for animals from different strains of the same species together; (2) for every species the same significant parameters are found in the models for 239Pu and in the models for 226Ra, and the only difference is in the value of the linear mutation coefficient; and (3) the toxicity ratio, when defined as the ratio of the linear mutation coefficients for 239Pu over 226Ra, has a relatively uniform value of approximately 8 for the species considered. This relatively constant ratio enables the development of a 239Pu model for humans that is based on the radium dial painters and the toxicity ratio for beagles. The model predictions agree well with published risk estimates based on other data and derived using alternative approaches. This has two important implications: (1) The two-mutation model appears to be a useful tool in translating from animal models to humans in a meaningful way; and (2) once a two-mutation model for humans has been derived, radiation risks can be calculated that depend on doses, dose rates and ages at exposure. Such a model therefore supplements published risk estimates that often lack such dependences.

Received: November 29, 2006; Accepted: April 27, 2007



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FIG. 1. Schematic representation of the two-mutation model used in this study: Sensitive normal cells (S) can be transformed into intermediate cells (I) at mutation rate μ1. The intermediate cells proliferate with a net growth advantage ε or become malignant (M) at mutation rate μ2. The malignant cells grow into tumors in a lag time tlag

FIG. 2. Examples of the model fit to the rat data. Panels a–c represent three groups of Sprague-Dawley rats from ref. (12) that were injected with different activities of 226Ra. Panels d–f give the joint fit of the Sprague-Dawley rats of ref. (12) and the F1 rats of ref. (13) for three groups injected with 239Pu

FIG. 3. Panel a: Model estimates of excess mortality per Bq 239Pu for varying age at exposure and total inhaled dose. Panel b: cross sections through (a) for ages 15 and 45 years; panel c: a cross section through (a) for a total dose of 5000 Bq

FIG. 4. Curve for excess mortality as a function of inhalation dose showing the nonlinear dose response in the two-mutation model derived for humans exposed to 239Pu. The nonlinearity necessitates a new definition of the toxicity ratio

FIG. 5. Panel a: Model estimates of excess mortality per Gy for varying age at (first) exposure and total dose to the skeleton. Panel b: Cross-sections through (a) for ages 15 and 45 years. Panel c: cross sections through (a) for a total dose of 0.3 and 0.8 Gy

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TABLE 1 Mouse Data Used for Modeling

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TABLE 2 Rat Data Used for Modeling

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TABLE 3 Beagle Data Used for Modeling

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TABLE 4 Human Data Used for Modeling

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TABLE 5 Preferred Models for Joint Fits of 226Ra- and 239Pu-Injected Mice

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TABLE 6 Preferred Models for Joint Fits of 226Ra- and 239Pu-Injected Rats

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TABLE 7 Estimates of Bone Cancer Mortality due to Plutonium

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TABLE 8 Model Calculations of Bone Cancer Mortality due to Inhaled Plutonium Activity

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TABLE 9 Model Calculations of Bone Cancer Mortality due to Plutonium Dose

 
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